Hot Topics in Cardio-Oncology 9781000793611, 9788770226288

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Ri ver Publ i shers S eri es i n B i ot echnol ogy and Medi cal Technol ogy Forum

HOT TOPICS IN CARDIO-ONCOLOGY

Editors: Valentina Mercurio Pasquale Pagliaro Claudia Penna

Carlo Gabriele Tocchetti

Hot topics in Cardio-Oncology

RIVER PUBLISHERS SERIES IN BIOTECHNOLOGY AND MEDICAL TECHNOLOGY FORUM Series Editors PAOLO DI NARDO University of Rome Tor Vergata Italy

PRANELA RAMESHWAR Rutgers University USA

Indexing: all books published in this series are submitted to the Web of Science Book Citation Index (BkCI) and to SCOPUS for evaluation and indexing Biotechnology & Medical Technology (BTMT) Forum is an international initiative aimed at disseminating the results of studies interfacing basic and translational medicine, biomaterials and applied engineering. BTMT Forum is committed to rapidly communicate the results of the scientific studies to scientists and the wider public worldwide. Peer-reviewed original comprehensive articles are published monthly on the basis of their novelty, relevance, interdisciplinary impact, and potential scientific and translational significance. Early outcomes from clinical trials are also published. The Forum publishes thorough authoritative reviews and commentaries on the most important issues and perspectives of cutting-edge research after a careful evaluation by the Editorial Board. Monographic books are also printed on specific topics of relevant concern under invitation by the Editorial Board or after independent proposals by potential book editors. Finally, BTMT Forum publishes a book series specifically intended for professionals eager to revitalize their acquaintance and students of different educational ages. BTMT Forum activities also involve the promotion of Congresses, Seminars, etc. Topics

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basic and translational medicine biomaterials applied engineering

For a list of other books in this series, visit www.riverpublishers.com

The NEC and You HotPerfect topicsTogether: in Cardio-Oncology A Comprehensive Study of the National Electrical Code

Editors Valentina Mercurio Department of Translational Medical Sciences, Federico II University, Naples, Italy Gregory P. Bierals Electrical Design Institute, USA

Pasquale Pagliaro

Department of Clinical and Biological Sciences, University of Turin, Italy

Claudia Penna Department of Clinical and Biological Sciences, University of Turin, Italy

Carlo Gabriele Tocchetti Department of Translational Medical Sciences, Interdepartmental Center of Clinical and Translational Research (CIRCET), Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy

River Publishers

Published 2021 by River Publishers

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Hot topics in Cardio-Oncology / by Valentina Mercurio, Pasquale Pagliaro, Claudia Penna, Carlo Gabriele Tocchetti. 2021 River Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval systems, or transmitted in any form or by any means, mechanical, photocopying, recording or otherwise, without prior written permission of the publishers. ©

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Contents

List of Figures

ix

List of Tables

xi

List of Contributors

xiii

List of Abbreviations

xvii

Introduction Valentina Mercurio, Pasquale Pagliaro, Claudia Penna, Carlo G Tocchetti

xxi

1 Inflammation in Cardio-Oncology Remo Poto, Giancarlo Marone, Flora Pirozzi, Alessandra Cuomo, Antonio Carannante, Maria Rosaria Galdiero, Carlo G Tocchetti, Valentina Mercurio, Gilda Varricchi 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Inflammation in Cardiac Injury and Repair . . . . . . . . . . 1.3 Immune Checkpoint Inhibitors . . . . . . . . . . . . . . . . 1.4 CAR-T Cell Therapy . . . . . . . . . . . . . . . . . . . . . 1.5 Inflammation at the Crossroad Between Cancer and Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Vascular Toxicity and Thromboembolic Risk in Cardio-Oncology Daniela Di Lisi, Giuseppina Novo 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Acute Coronary Syndrome (ACS) and Coronary Artery Diseases (CAD) . . . . . . . . . . . . . . . . . . . . 2.3 Other Drugs that Cause Myocardial Infarction and Coronary Artery Diseases . . . . . . . . . . . . . . . . . . . v

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2 2 4 8 9 12 21 21 22 25

vi Contents 2.4 Arterial Hypertension . . . . . . . . . . . . . 2.5 Peripheral Artery Occlusive Diseases . . . . . 2.6 Pulmonary Hypertension . . . . . . . . . . . 2.7 Stroke . . . . . . . . . . . . . . . . . . . . . 2.8 Thromboembolic Risk and Atrial Fibrillation . 2.9 Prevention and Treatment of Vascular Toxicity References . . . . . . . . . . . . . . . . . . . . . .

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3 Hypertensive Oncologic Patients Giacomo Tini, Massimo Volpe, Paolo Spallarossa 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . 3.2 Implications of Arterial Hypertension in Patients Undergoing Anticancer Treatments . . . . . . . . . . 3.2.1 Anthracyclines . . . . . . . . . . . . . . . . . 3.2.2 Carfilzomib . . . . . . . . . . . . . . . . . . 3.2.3 Anti-vascular endothelial growth factor agents 3.3 Management of Arterial Hypertension in Oncologic Patients . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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4 Cardiac Surgery and Percutaneous Coronary Intervention in Patients With Cancer Fabrizio D’Ascenzo, Stefano Salizzoni, Ovidio De Filippo, Guglielmo Gallone, Francesco Bruno, Mauro Rinaldi, Gaetano Maria De Ferrari 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 The complex interplay between ACS and cancer: bench and pharmacological data . . . . . . . . . 4.1.2 The complex interplay between ACS and cancer: the role of the disease . . . . . . . . . . . . . . . 4.1.3 The complex interplay between ACS and cancer: the role of chemotherapy and of radiotherapy. . . 4.1.4 The complex interplay between ACS and cancer: clinical data . . . . . . . . . . . 4.1.5 The complex interplay between cardiac surgery and cancer: clinical data . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5 Cancer Therapy-Induced Arrhythmias Davide Castagno, Vincenzo Cusenza, Gaetano Maria De Ferrari 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .

63 63

Contents vii

5.1.1 5.1.2 5.1.3

Epidemiology . . . . . . . . . . . . . Etiology and Pathogenesis. . . . . . . Diagnosis, Physical Examination, and Diagnostic Tests . . . . . . . . . . . . 5.1.4 Clinical Characteristics . . . . . . . . 5.1.5 Treatment . . . . . . . . . . . . . . . 5.1.6. Prophylaxis . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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67 69 69 76 78

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6 Cancer in the Heart Failure Population Alessandra Cuomo, Flora Pirozzi, Francesca Paudice, Giovanni Perrotta, Giovanni D’Angelo, Antonio Carannante, Carlo Gabriele Tocchetti, Valentina Mercurio, Pietro Ameri 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 6.2 Heart Failure and New Onset Cancer: Epidemiology . . 6.3 Mechanisms of Cancer Development in the Heart Failure Population . . . . . . . . . . . . . . . . 6.4 Cancer in Heart Failure Patients: Clinical Implications . 6.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology Christian Cadeddu Dessalvi, Martino Deidda, Antonio Noto, Giuseppe Mercuro 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 7.2 Metabolomics . . . . . . . . . . . . . . . . . . . . . . 7.3 Metabolomics in Cardio-Oncology . . . . . . . . . . . 7.4 Metabolomics Profiling Cardioprotective Strategies . . 7.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Imaging in Cardio-Oncology Roberta Manganaro, Concetta Zito 8.1 Introduction . . . . . . . . . . . . . . . . 8.2 Conventional Echocardiography . . . . . 8.2.1 LV systolic and diastolic function . 8.2.2 RV function . . . . . . . . . . . . 8.2.3 Valvular heart disease . . . . . . . 8.2.4 Pericardial disease . . . . . . . . . 8.3 Advanced Echocardiography . . . . . . . 8.3.1 Myocardial deformation imaging .

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viii Contents 8.4 8.5

Three-Dimensional Echocardiography (3DE). . . . . . . . Assessment of Cardiotoxicity Risk and Echocardiographic Surveillance According to Anticancer Treatment . . . . . . 8.6 Other imaging modalities . . . . . . . . . . . . . . . . . . 8.6.1 Cardiac Magnetic Resonance . . . . . . . . . . . . 8.7 Cardiac Nuclear Imaging . . . . . . . . . . . . . . . . . . 8.8 Multimodality Imaging in Screening and Follow-up in Radiotherapy . . . . . . . . . . . . . . . . . 8.8.1 Pericardial disease . . . . . . . . . . . . . . . . . . 8.8.2 Myocardial dysfunction . . . . . . . . . . . . . . . 8.8.3 Valvular heart disease (see also above) . . . . . . . 8.8.4 Coronary artery disease . . . . . . . . . . . . . . . 8.9 Conclusions and Future Directions . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Venous Thromboembolism in Cardio-Oncology Ciro Santoro, Mario Enrico Canonico 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 9.2 Biological Mechanism of Cancer-Related Thrombosis . 9.3 Epidemiology and Risk Stratification . . . . . . . . . . 9.4 Clinical Presentation . . . . . . . . . . . . . . . . . . 9.5 Recurrent Venous Thrombosis and Treatment in Cancer Population . . . . . . . . . . . . . . . . . . . . 9.6 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . 9.7 Thromboprophylaxis . . . . . . . . . . . . . . . . . . 9.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusions and Remarks Valentina Mercurio, Pasquale Pagliaro, Claudia Penna, Carlo G Tocchetti References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

163

Index

165

About the Editors

167

164

List of Figures

Figure 1.1 Figure 2.1 Figure 3.1

Figure 4.1 Figure 4.2 Figure 4.3 Figure 6.1 Figure 7.1 Figure 9.1

Figure 9.2

Inflammation at the intersection of the anticancer action and cardiac side effects of major oncological treatments. . . . . . . . . . . . . . . . . 4 Vascular events caused by anticancer drugs. . . . . . 22 Algorithm for evaluation of blood pressure and management of arterial hypertension in cancer patients [modified from Spallarossa et al. (Russo et al. 2019)]. . . . . . . . . . . . . . . . . . 46 Virchow’s triad in cancer patients (plts: platelets). . . 52 Incidence of MI and of stroke/TIA according to classes of drugs. . . . . . . . . . . . . . . . . . . . . 54 Incidence and timing of MI according to kind of cancer (Navi et al. [13]). . . . . . . . . . . . . . . . 56 Graphic summary of the link between heart failure and cancer . . . . . . . . . . . . . . . . . . . 85 Timing of cardiotoxicity detection by conventional biomarkers and metabolomics. . . . . . . . . . . . . 108 Synergic interaction between primary tumor and activated platelets to develop clot formation due to FXa, thrombin, and TF release from cancer cells. . . . . . . . . . . . . . . . . . . . . . . 149 (A) Not-occlusive deep venous thrombosis of the right common femoral vein with no compression ultrasound (left panel) and with compression ultrasound (right panel, CUS positive, only partial compressibility). (B) On the left, superficial venous thrombosis of the right greater saphenous vein (CUS positive). On the right, superficial venous thrombosis of collaterals of the right greater saphenous vein. . . . . . . . . . . 152

ix

List of Tables

Table 2.1 Table 8.1 Table 8.2 Table 8.3 Table 8.4 Table 9.1 Table 9.2

Vascular events and anticancer drugs. . . . . . . . Echocardiographic parameters relevant for cardiooncology surveillance. . . . . . . . . . . . . . . . Assessment of cardiotoxicity risk. . . . . . . . . . Echocardiographic surveillance during and after anthracycline chemotherapy. . . . . . . . . . . . . Echocardiographic surveillance during and after HER2-targeted therapies. . . . . . . . . . . . Risk factors for venous thrombosis. . . . . . . . . Predictive model for chemotherapy-associated venous thrombosis. . . . . . . . . . . . . . . . . .

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List of Contributors

Ameri Pietro, Cardiovascular Disease Unit, IRCCS Italian Cardiovascular Network, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Internal Medicine, University of Genova, Genoa, Italy Antonio Carannante, Department of Translational Medical Sciences, Federico II University, Naples, Italy Bruno Francesco, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Canonico Mario Enrico, Department of Advanced Biomedical Science, Federico II University Hospital, Naples, Italy Castagno Davide, Division of Cardiology, Department of Medical Sciences, “Città della Salute e della Scienza Hospital,” University of Turin, Italy Cuomo Alessandra, Department of Translational Medical Sciences, Federico II University, Naples, Italy Cusenza Vincenzo, Division of Cardiology, Department of Medical Sciences, “Città della Salute e della Scienza Hospital,” University of Turin, Italy De Ferrari Gaetano Maria, Division of Cardiology, Department of Medical Sciences, “Città della Salute e della Scienza Hospital,” University of Turin, Italy De Filippo Ovidio, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Deidda Martino, Department of Medical Sciences and Public Health − University of Cagliari, Italy

xiii

xiv List of Contributors Dessalvi Christian Cadeddu, Department of Medical Sciences and Public Health − University of Cagliari, Italy D’Angelo Giovanni, Department of Translational Medical Sciences, Federico II University, Naples, Italy D’Ascenzo Fabrizio, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Galdiero Maria Rosaria, Department of Translational Medical Sciences, Federico II University, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy; WAO Center of Excellence, Naples, Italy; Institute of Experimental Endocrinology and Oncology “G. Salvatore” (IEOS), National Research Council (CNR), Naples, Italy Gallone Guglielmo, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Lisi Daniela Di, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Cardiology Unit, University Hospital P. Giaccone, Palermo, Italy Manganaro Roberta, Department of Clinical and Experimental Medicine, Unit of Cardiology − University of Messina, Messina Italy Marone Giancarlo, Department of Public Health, Section of Hygiene, University of Naples Federico II, Naples, Italy; Monaldi Hospital Pharmacy, Naples, Italy Mercurio Valentina, Department of Translational Medical Sciences, Federico II University, Naples, Italy Mercuro Giuseppe, Department of Medical Sciences and Public Health − University of Cagliari, Italy Noto Antonio, Department of Medical Sciences and Public Health − University of Cagliari, Italy Novo Giuseppina, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Cardiology Unit, University Hospital P. Giaccone, Palermo, Italy

List of Contributors xv

Pagliaro Pasquale, Departiment of Clinical and Biological Sciences, University of Turin, Torino, Italy; Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy Paudice Francesca, Department of Translational Medical Sciences, Federico II University, Naples, Italy Penna Claudia, Departiment of Clinical and Biological Sciences, University of Turin, Torino, Italy; Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy Perrotta Giovanni, Department of Translational Medical Sciences, Federico II University, Naples, Italy Pirozzi Flora, Department of Translational Medical Sciences, Federico II University, Naples, Italy Poto Remo, Department of Translational Medical Sciences, Federico II University, Naples, Italy 1 Rinaldi Mauro, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Salizzoni Stefano, Division of Cardiology, Department of Medical Science, Città della Salute e della Scienza, University of Turin, Italy; Division of Cardiac Surgery, Città della Salute e della Scienza, University of Turin, Italy Santoro Ciro, Department of Advanced Biomedical Science, Federico II University Hospital, Naples, Italy Spallarossa Paolo, Clinic of Cardiovascular Diseases, IRCCS Ospedale Policlinico San Martino, Genova, Italy Tini Giacomo, Cardiology, Azienda Ospedaliero-Universitaria Sant’Andrea, University of Rome Sapienza, Rome, Italy Tocchetti Carlo Gabriele, Department of Translational Medical Sciences, Federico II University, Naples, Italy; Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy; Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy; Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy

xvi List of Contributors Varricchi Gilda, Department of Translational Medical Sciences, Federico II University, Naples, Italy;Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy; WAO Center of Excellence, Naples, Italy; Institute of Experimental Endocrinology and Oncology “G. Salvatore” (IEOS), National Research Council (CNR), Naples, Italy Volpe Massimo, Cardiology, Azienda Ospedaliero-Universitaria Sant’Andrea, University of Rome Sapienza, Rome, Italy Zito Concetta, Department of Clinical and Experimental Medicine, Unit of Cardiology − University of Messina, Messina Italy

List of Abbreviations

18F-FDG 1H NM 2-D Echo 2D 3D 3DE 5-FU AC ACEi ACS AF Akt AMI AMPK ANP AOEs AP-1 APC ARBs AS ATEs BAD Bcr BNP BP CAD CANTOS trial CAR-T CCB CHARM

18-fluorodeoxyglucose proton nuclear magnetic resonance spectroscopy two-dimensional echocardiography two-dimensional; three-dimensional; three-dimensional echocardiography 5-fluorouracil anthracyclines angiotensin converting enzyme-inihibitors acute coronary syndrome Atrial fibrillation acute myocardial infarction Adenosine monophosphate-activated protein kinase atrial natriuretic peptide arterial occlusive events activator protein 1 antigen-presenting cells angiotensin receptor blockers Aortic Stenosis arterial thromboembolic events Bcl-2-associated death promoter breakpoint cluster region; brain natriuretic peptide blood pressure coronary artery disease Canakinumab Anti-Inflammatory Thrombosis Outcome Study trial cell therapy uses T cells calcium channel blockers Candesartan in Heart Failure: Assessment of Mortality and Morbidity trial xvii

xviii List of Abbreviations CK CK-MB CMP CMR CREB CRP CRS CSF-1R CT CTLA- 4 cTn CTRCD CTX CV CVD CY DAMPs DAPT DOXO DSI DZR ECG EDV EF EMT eNOS ESV FAC FDA FLT3 F-THP GC-MS GCS GISSI-HF trial GLS GnRH H2O2 HER2 HF

creatine kinase myocardial CK cardiomyopathy; cardiac magnetic resonance cAMP response element-binding protein C-reactive protein cytokine release syndrome colony-stimulating factor-1 receptor computed tomography Cytotoxic-T-lymphocyte-associated antigen 4 Cardiac troponins Cancer Therapy-Related Cardiac Dysfunction cardiotoxicity cardiovascular; Cardiovascular disease cyclophosphamide danger-associated molecular patterns double antiplatelet therapy Doxorubicin Doppler strain imaging dexrazoxane Electrocardiogram end-diastolic volume; ejection fraction epithelial to mesenchymal transition endothelial nitric oxide synthase end-systolic volume; fractional area change; Food and Drug Administration FMS-like tyrosine kinase-3 free THP gas-chromatography coupled with mass spectrometry global circumferential strain; Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure global longitudinal strain; gonadotropin-releasing hormone hydrogen peroxide human epidermal growth factor receptor 2; heart failure

List of Abbreviations xix

HFrEF hiPSC-CMs HO• HR HR-MAS NMR HTN ICI ICOS-1 IFN-γ IKr IL IL-6R iNOS irAEs IVC LC-MS LDH LGE LPC L-THP LV LVEF LVEF mAbs MAPKs MetS MI MTX NF- kB NK NO pro-BNP NT-proBNP O−2 PAD PAD PAH PCI

Heart Failure with reduced ejection fraction human induced pluripotent stem cell-derived cardiomyocytes hydroxyl radical hazard ratio high-resolution magic-angle-spinning nuclear magnetic resonance techniques hypertension Immune Checkpoint Inhibitors International Cardio Oncology Society-One trial interferon-gamma Potassium rapid inward rectifier interleukin soluble receptor IL-6 inducible nitric oxide synthase immune-related adverse events inferior vena cava; liquid chromatography mass spectrometry lactate dehydrogenase late gadolinium enhancement lysophosphatidylcholine liposome powder THP left ventricular Left ventricle EF left ventricular ejection fraction; monoclonal antibodies mitogen-activated protein kinases metabolic syndrome myocardial infarction methotrexate nuclear factor-κB natural killer nitric oxide pro-B-Type natriuretic peptide N-terminal portion-proBNP superoxide anion peripheral arterial occlusive disease peripheral artery disease; pulmonary arterial hypertension Percutaneous Coronary Interventions

xx List of Abbreviations PDGFR PGE2 PI3Ks PKC PRADA Akt/PKB RAAS RIHD ROS RT RV RVEF SD SEER SNS SOLVD SpD SSFP STE SUCCOUR TAM TAPSE TAVI TDI THP TKI TLR TNF TR TSP2 UPLC–QTOF-MS VEGF VEGFi VHD vWf βARs

Platelet-derived growth factor receptor prostaglandin E2 Phosphoinositide 3-kinases protein kinase C primary prevention trial with Candesartan trial protein kinase B Akt/PKB renin-angiotensin-aldosterone system radiation-induced” heart disease Reactive oxygen species radiotherapy right ventricular; right ventricular ejection fraction; male Sprague Dawley rat Surveillance Epidemiology and End Results sympathetic nervous system Studies of Left Ventricular Dysfunction trial. spinochrome D steady-state free precession sequence. speckle-tracking echocardiography Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcome trail tumor-associated macrophage tricuspid annular plane systolic excursion; transcatheter aortic valve implantations Tissue Doppler Imaging anthracycline pirarubicin tyrosine kinase inhibitors toll-like receptor . tumour necrosis factor tricuspid regurgitation. thrombospondin-2 ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry vascular endothelial growth factor vascular endothelial growth factor inhibitor valvular heart disease. von Willebrand factor β-adrenergic receptors

Introduction

Valentina Mercurio, MD, PhD, FISC1; Pasquale Pagliaro, MD, PhD2,3, Claudia Penna, BSc, PhD2,3; Carlo G Tocchetti, MD, PhD, FHFA, FISC1,4,5,6 Department of Translational Medical Sciences, Federico II University, Naples, Italy 2 Departiment of Clinical and Biological Sciences, University of Turin, Torino, Italy 3 Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy 4 Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy 5 Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy 6 Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy 1

The growing advances in the field of cancer therapies are leading to a progressive decrease in mortality rates for several cancers. On the other side, such valuable therapies have shown a wide spectrum of cardiotoxicities. Indeed, the cardiovascular system represents a possible target of several antineoplastic drugs, with different manifestations: ischemic vasospasm, thromboembolism, hypertension, arrhythmias, and ventricular dysfunction, leading to heart failure. Asymptomatic reduction in left ventricular systolic function and heart failure are the most frequent complications of long-term oncological regimens. Such cardiotoxic manifestations can develop or persist even after recovery from cancer. Chemotherapy-induced cardiotoxicity becomes even more relevant when we consider that elderly patients may have more “opportunity” to develop cancer and may already present with pre-existing chronic diseases and cardiovascular comorbidities (such as hypertension, obesity, diabetes, dyslipidemia, but also coronary artery xxi

xxii Introduction disease and heart failure) in which inflammation (better “inflammaging”) and oxidative stress play an important role. Several studies have investigated the possible mechanisms underlying the development of cardiovascular adverse events with anticancer therapies. For instance, it is well-known that anthracyclines can cause cardiotoxicity through an increase in oxidative damage in the myocardium. On the other hand, biological therapies led to the discovery of other possible mechanisms of cardiotoxicity: some inhibitors of biological pathways can also interfere with intracellular signaling with a key role in the cardiovascular system. Finally, in the last years, an increase in the incidence of myocarditis, especially with the use of immune checkpoint inhibitors, has been observed, suggesting the importance of immune-inflammatory mechanisms in the development of cardiotoxicity. Multiple intersections between thrombosis and cancer exist, and balanced antithrombotic therapies need to be considered. It is fundamental to detect cardiotoxicity as early as possible. In this regard, cardiovascular imaging, spanning from echocardiography to cardiac magnetic resonance, has acquired a fundamental role in the early detection and the monitoring of cardiotoxicity. Finally, concerning the use of biomarkers for the detection of cardiotoxicity, the new -omics sciences are emerging in this context with promising results. In particular, metabolomics has provided the first encouraging results in animal models, and the first data in small clinical trials show the ability of metabolomics to identify patients who are undergoing significant early cardiovascular toxicity. The chapters of this book emphasize the above-mentioned concepts, providing the readers with the latest advances and insights in the everexpanding field of cardio-oncology.

1 Inflammation in Cardio-Oncology Remo Poto, MD1; Giancarlo Marone, PharmaD2,3; Flora Pirozzi, MD, PhD1; Alessandra Cuomo, MD1; Antonio Carannante, MD1; Maria Rosaria Galdiero, MD, PhD1,4,5,6; Carlo G Tocchetti, MD, PhD, FHFA, FISC1,4,7,8; Valentina Mercurio, MD, PhD, FISC1; Gilda Varricchi, MD, PhD1,4,5,6 Department of Translational Medical Sciences, Federico II University, Naples, Italy 2 Department of Public Health, Section of Hygiene, University of Naples Federico II, Naples, Italy 3 Monaldi Hospital Pharmacy, Naples, Italy 4 Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy 5 WAO Center of Excellence, Naples, Italy 6 Institute of Experimental Endocrinology and Oncology “G. Salvatore” (IEOS), National Research Council (CNR), Naples, Italy 7 Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy 8 Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy 1

*Correspondence to: Carlo Gabriele Tocchetti, MD, PhD, FHFA, FISC, UOS Gestione del paziente oncologico in Medicina Interna Dipartimento di Scienze Mediche Traslazionali Centro Interdipartimentale di Ricerca Clinica e Traslazionale (CIRCET) Centro interdipertimentale di ricerca per l’Ipertensione Arteriosa e Patologie Associate (CIRIAPA) Universita’ degli Studi di Napoli Federico II, Via Pansini 5 80131 Napoli, ITALY, Phone +39-081-746-2242, Fax +39-081-746-2246, [email protected] 1

2 Inflammation in Cardio-Oncology KEYWORDS: Cancer; Cardiovascular diseases; Cardio-oncology; Immune Checkpoint inhibitors; Inflammation.

1.1 Introduction Inflammation contributes to the pathophysiological features of cardiovascular disease (CVD) and cancer and is involved in the initiation, progression, and poor prognosis of both diseases (Libby and Kobold 2019). With the prolongation of life expectancy, both CVD and cancer are rising in the elderly population, requiring a deeper understanding of their molecular mechanisms (de Boer et al. 2020; Cuomo et al. 2021). Indeed, aging is characterized by an increase in the prevalence of several chronic and degenerative diseases, such as cancer and CVDs, with the involvement of oxidative stress and cellular senescence (Mercurio et al. 2020). Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, which participates in the development of frailty, disability, cancer, and CV disease. The name inflammaging indicates a broad immune dysregulation in elderly people, in which persistently increased levels of circulating pro-inflammatory mediators [such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α] and of the biomarker C-reactive protein (CRP) are associated with a blunted immune response (Liberale et al. 2020). The chronic low-grade pro-inflammatory state contributes to the activation of leukocytes, endothelial and vascular smooth muscle cells, thus accelerating vascular aging and atherosclerosis and leading to increased incidence of CVD. Therefore, inflammation has emerged as an independent CV risk factor and pathogenic contributor to CVD. Thanks to recent advances in pharmacological therapies, CV death and, in particular, sudden cardiac death (Shen et al. 2017; Conrad et al. 2019; Moliner et al. 2019) have been reduced among HF patients. However, this has led to an increased burden of comorbidities, including cancer (Tini et al. 2020). In parallel, the analogue improvement of oncological management and treatments has considerably decreased the mortality linked to several cancers, while concomitantly increasing the comorbidity burden of oncological elderly patients. In this context, cancer and CVDs share common systemic pathogenic inflammatory pathways and mechanisms (de Boer et al. 2020; Tocchetti et al. 2020).

1.2 Inflammation in Cardiac Injury and Repair Importantly, inflammation plays a key role in cardiac injury and repair. During cardiac ischemia, several endogenous ligands that act as “danger signals”,

1.2 Inflammation in Cardiac Injury and Repair 3

also called danger-associated molecular patterns (DAMPs), are released upon injury and modulate inflammation (Arslan et al. 2011). For instance, myocardial injury, through the exposure/release of cardiac antigens, triggers a persistent cardiac T-cell response with subsequent production of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, thus contributing to a self-perpetuating inflammatory state that underlies adverse tissue remodeling (Prabhu and Frangogiannis 2016; Frantz et al. 2018; de Boer et al. 2019). In particular, TNF-α is a potent activator of nuclear factor-κB (NF- κB), a primary mediator of inflammation in cancer (Sethi et al. 2008; Aggarwal et al. 2012). Downstream signaling includes the over-activation of mitogen-activated protein kinases (MAPKs) and the abnormal stimulation of NF-κB. Besides, the consequent overexpression of pro-inflammatory cytokine and chemokine genes triggers inflammatory cells and causes oxidative stress, thus leading to DNA damage and increase in the likelihood of malignant mutations and cancer incidence modifying the tissue microenvironment (White et al. 2013). The inflammatory response also enables the induction of regenerative processes following acute myocardial injury, leading to heart failure (HF). Blockade of the pro-inflammatory cytokine IL-1β with canakinumab, an interleukin-1β neutralizing monoclonal antibody, was shown to significantly reduce the rate of recurrent CV events in patients with previous myocardial infarction (Canakinumab Anti-Inflammatory Thrombosis Outcome Study – CANTOS trial) (Ridker et al. 2017b). The inflammatory response is also involved in cardiotoxicity from anticancer drugs (Tocchetti et al. 2019; Tocchetti et al. 2020, Figure 1.1). Doxorubicin-induced damage also leads to the upregulation of proinflammatory toll-like receptor 4 (TLR4) in macrophages (Wang et al. 2016), higher levels as TNF-α and IL-6 and reduced levels of the anti-inflammatory cytokine IL-10 (Pecoraro et al. 2016). Cardiac function was preserved, and survival improved in TLR2 knock-out mice after DOXO exposure compared to wild-types (Nozaki et al. 2004). DOXO also induces local modulators of inflammation and fibrosis, produced by both macrophages and fibroblasts. In addition, increased production of the matricellular protein thrombospondin-2 (TSP2) is protective in mice treated with DOXO. Augmented myocyte damage in the absence of TSP-2 was linked with impaired activation of the Akt signaling pathway. Importantly, inhibition of Akt phosphorylation in cardiomyocytes reduced TSP-2 expression, revealing a single feedback loop between Akt and TSP-2 (van Almen et al. 2011). Furthermore, CCL2/CCR2-dependent recruitment of functional antigenpresenting cells (APC) into tumor tissue is an expected therapeutic effect of anthracyclines (Ma et al. 2014).

4 Inflammation in Cardio-Oncology

1.3 Immune Checkpoint Inhibitors For decades, oncologists have been developing strategies to modulate inflammation in order to achieve therapeutic anticancer immune responses (Lesterhuis et al. 2011). Cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints (i.e., CTLA-4 and PD-1/ PD-L1) have revolutionized antineoplastic treatments and stand out as the biggest example of the involvement of inflammatory processes in cardiooncology; see Figure 1.1.). Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), PD-1, and its ligand PD-L1 are crucial regulators of the immune response (Varricchi et al. 2017; Lyon et al. 2018; Hu et al. 2019).

Figure 1.1 (Reproduced with permission from Tocchetti et al. 2020) Inflammation at the intersection of the anticancer action and cardiac side effects of major oncological treatments.

1.3 Immune Checkpoint Inhibitors 5

CTLA-4, a co-inhibitory molecule expressed on activated CD4+/CD8+ T-cells, competes with CD28 in binding CD80 and/or CD86 to attenuate T-cell activation (Linsley et al. 1990). Moreover, PD-1 expressed on T-cells, natural killer (NK) cells, B cells, monocytes, tumor-associated macrophage (TAM), immature Langerhans cells and cardiomyocytes, and its ligand PD-L1, inhibits the immune response by suppressing T-cell proliferation and reducing cytokine production (Swaika et al. 2015). The expression of PD-L1 is an essential immune evasion mechanism by which cancer cells escape the host immune response. Accordingly, several checkpoint inhibition strategies have been developed (Nguyen and Ohashi 2015; Sharma and Allison 2015, 2020; Le Mercier, Lines, and Noelle 2015). Monoclonal antibodies directed against CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab, and cemiplimab), and PD-L1 (atezolizumab, avelumab, and durvalumab) block these immune checkpoints and unleash anti-tumor immunity, leading to tumor cell death through cytolytic molecules, such as TNF-α, granzyme B, and IFN-γ (Varricchi et al. 2017). Immune checkpoints play a central role in the maintenance of selftolerance (Tivol et al. 1995; Waterhouse et al. 1995; Nishimura et al. 1999; van Elsas et al. 2001; Fritz and Lenardo 2019). Inhibition of these pathways with ICIs, either alone or in combination, can lead to imbalances in immunologic tolerance that result in a broad spectrum of immune-related adverse events (irAEs) (Zimmer et al. 2016; Puzanov et al. 2017; Tocchetti et al. 2018). Cardiac irAEs due to ICIs (such as myocarditis, conduction abnormalities, cardiomyopathy, pericarditis, Takotsubo syndrome, and cardiac failure) are rare (Wang et al. 2017; Ederhy et al. 2018; Yang and Asnani 2018). The true incidence of cardiac irAEs due to ICIs is unknown; current estimates suggest less than 1% of patients (Johnson et al. 2016). Cardiac irAEs appear more frequently in patients treated with ipilimumab compared to PD-1 inhibitors (Johnson et al. 2016). The pathophysiologic mechanisms of ICI-associated cardiotoxicity are still elusive and remain to be clarified. PD-1 and PD-L1 are expressed on the surface of murine and human cardiomyocytes (Dong et al. 1999; Freeman et al. 2000; Nishimura et al. 2001; Johnson et al. 2016). Experimental studies have demonstrated that CTLA-4 and PD-1 deletion or inhibition can cause autoimmune myocarditis with lymphocytic infiltration of cytotoxic T-cells (Tivol et al. 1995; Okazaki et al. 2003; Grabie et al. 2007; Wang et al. 2010;). Läubli et al. reported that lymphocytic infiltrates were characterized by the same T-cell lineage, which was present in both myocardium and tumor (Läubli et al. 2015). The latter finding suggests the existence of an expansion of a T-cell clone targeting a distinct but homologous antigen shared by the

6 Inflammation in Cardio-Oncology heart and the tumor. Johnson et al. (2016) found that T-cell clonal activation occurs in response to a common antigen, and the same T-cell clone identified within myocardium was also present in tumor and skeletal muscle. Several factors may play a role in ICI-associated cardiotoxicity. In patients with CTLA-4 polymorphisms and concomitant cardiac risk factors, exposure to infectious agents can trigger a mechanism of molecular mimicry and can lead more easily to irAEs. Likely, in myocarditis patients, various stressors could play a contributing role (Giza et al. 2017). Gil-Cruz et al. (2019) demonstrated that progression of autoimmune myocarditis to lethal heart disease depends on cardiac myosin-specific Th17 cells imprinted in the intestine by a peptide mimic derived from a commensal Bacteroides species. Interestingly, they observed a significantly elevated Bacteroides-specific CD4+ T cell and B cell responses in human myocarditis. Furthermore, antibiotic therapy led to effective prevention of lethal disease in mice. The latter findings suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible patients (Portig et al. 2009). It is possible to speculate that targeting the microbiome of genetically predisposed patients undergoing ICIs with antibiotics may reduce the incidence and severity of inflammatory cardiomyopathy (GilCruz et al. 2019). This innovative approach is compatible with the increasing evidence that the inter-individual difference in gut microbiota is a source of the heterogeneity in immune-therapeutic efficacy and toxicity of ICIs (Vétizou et al. 2015; Zitvogel et al. 2018). Further studies in precision cardiooncology are needed to elucidate individual and concurrent pathophysiologic mechanisms behind the cardiovascular toxicity of ICIs. The holistic approach to cardiovascular management of patient candidates to ICI therapy requires a close collaboration among cardiologists, oncologists, and immunologists and is mandatory to stratify baseline risk and plan the best therapeutic approach for each patient (Lyon et al. 2018, 2020). Currently, there are no specific predictors of development of severe or mild cardiac toxicity caused by ICIs. Moreover, it is still unclear whether pre-existing risk factors might affect the incidence and severity of cardiac irAEs (Upadhrasta et al. 2019). Patients should be informed and alerted on potential development of ICI cardiotoxicity. These procedures represent a crucial component of preventive strategies before starting immunotherapy. Patients should be informed about signs and symptoms associated with cardiac toxicity and the need, especially in high-at-risk patients, for an in-depth screening and close surveillance (Hu et al. 2019; Lyon et al. 2018, 2020). Prospective cardiovascular evaluation seems to be necessary to detect potential cardiotoxicity. Hence, screening with a higher level of vigilance is

1.3 Immune Checkpoint Inhibitors 7

warranted before starting immunotherapy in patients with a known history of heart disease. It should be pointed out that novel strategies are needed to better identify high-at risk patients since conventional risk stratification algorithms such as Framingham risk score may underestimate cardiovascular risk in patients with cancer. Pharmacological history should be assessed since many cancer patients have already received multiple cardiotoxic treatments before starting ICIs, such as anthracyclines (Mercurio et al. 2019), anti-ErbB2 drugs (de Lorenzo et al. 2018), RAF and MEK inhibitors (Heinzerling et al. 2019), tyrosine kinase inhibitors (Tocchetti et al. 2013; Sharma et al. 2017; Dobbin et al. 2018), and radiotherapy (Kirova et al. 2020). Importantly, these treatments can lead to the release/exposure of cardiac antigens with subsequent organ-specific immune responses, initially subclinical, which can be amplified by the administration of ICIs. Phenotyping both tumor antigen profiles and pre-treatment T-cell clones could contribute to baseline risk assessment (Lyon et al. 2018). The assessment of pre-existing autoimmune diseases in cancer patients is an important issue. Previous clinical trials examining the safety and efficacy of ICIs have excluded patients with pre-existing autoimmune disorders. Therefore, the real incidence of flares of autoimmune disease cannot be estimated from these trials. Recent studies have started to evaluate the safety and efficacy of ICIs in patients with cancer and pre-existing autoimmune diseases. Tison et al. (2019) reported that 71% of patients experienced irAEs and 21% discontinued treatments. Inflammatory flares of the pre-existing autoimmune disease occurred in 47% of patients. Salem et al. (2018) reported that males appear to be at higher risk of developing cardiovascular events compared to females. This apparent sex dysmorphism could be explained by the fact that women have a higher incidence of autoimmune diseases and lower risk of cardiovascular diseases. For this reason, they are often excluded from clinical trials with ICIs, underestimating the true incidence of cardiac toxicity in women. Sex differences on cardiac toxicity during ICI remain controversial; therefore, further studies on this association are needed (Varricchi et al. 2018). Baseline measurement of circulating cardiovascular biomarkers (i.e., troponin I or T, brain natriuretic peptide [BNP] or N-terminal pro-B-Type natriuretic peptide [NT pro-BNP], total CK, CRP, and fasting lipid profile) is mandatory in patient candidate for ICIs (Pudil et al. 2020). Electrocardiogram (ECG) and two-dimensional echocardiography (2D Echo) are recommended in patients with history or symptoms of cardiovascular disease (Čelutkienė et al. 2020). Moreover, it is essential to optimize the cardiovascular therapy in all patients.

8 Inflammation in Cardio-Oncology Precision cardio-oncology, through multi “-omics” techniques, will help identify high-at-risk patients and personalize the clinical approach (Brownet al. 2020). At present, the impact of these techniques on clinical practice remains unknown. Novel precise and cost-effective risk prediction tools are emerging, with the need to identify patients who will benefit from closer monitoring and improve therapy decisions of cardiac toxicities. In this context, identification of gene polymorphisms leading to deficiency or dysfunction of CTLA-4, PD-1, or PD-L1 could be suggested in each patient since they are associated with myocarditis or cardiomyopathy and other autoimmune conditions in human and mice (Wang et al. 2010; Chen et al. 2013; Song et al. 2013; Wang et al. 2017). Integration of multiple systems including genomics, transcriptomics, proteomics, metabolomics, microRNA, microbiomics, and environmentomics could identify a fingerprint/signature unique to each patient, profiling a specific individual risk of cardiotoxicity (Brown et al. 2020). Radiotherapy and immunotherapy could have a synergic effect in developing adverse events. For instance, administration of ICIs in patients with lung cancer after thoracic radiotherapy might trigger pericardial diseases due to the release of potentially shared antigens recognized by T-cells. Salem et al. (2018) showed that pericarditis was over-reported in lung cancer patients treated with anti-PD-1 or anti-PD-L1 therapy and radiotherapy.

1.4 CAR-T Cell Therapy More recently, engineered T cells with chimeric antigen receptors (CAR-T cells; Figure 1.1) have been approved by the U.S. Food and Drug Administration (FDA) as the first genetically modified autologous T-cell that targets CD-19. A CAR is a recombinant receptor protein that has been engineered to activate T cells upon recognition of a specific antigen, resulting in the killing of target cells. CARcell therapy uses T cells engineered with CARs for cancer therapy. CD19 CAR-T cell therapies represent a new breakthrough in the treatment of relapsing and refractory hematological malignancies (Park et al. 2016; Salter et al. 2018). CD19 is a suitable target for CAR-T cells because it is expressed by B-cell malignancies but not by normal essential tissues. However, this promising therapy is associated with serious, potentially lifethreatening events (Park et al. 2016). In particular, cytokine release syndrome (CRS) and neurotoxicity are associated with CD19 CAR-T cell therapies (Brudno and Kochenderfer 2016; Neelapu et al. 2017; Schuster et al. 2017). CRS is a systemic inflammatory response due to the widespread release of inflammatory cytokines (IL-2, soluble IL-2Rα, interferon-gamma, IL-6,

1.5 Inflammation at the Crossroad Between Cancer and Cardiovascular Diseases

9

soluble IL-6R, and granulocyte-macrophage colony-stimulating factor) and chemokines by activated lymphocytes or myeloid cells. It is associated with the activation of CAR-T cells and can be characterized by fever, hypotension, capillary leak, coagulopathy, and severe organ dysfunction. Recent evidence suggested that CAR-T cell therapies are also associated with cardiovascular toxicity (Burstein et al. 2018; Fitzgerald et al. 2017). It is reasonable that cardiovascular toxicities observed during CD19 CAR-T cell therapy are a direct consequence of the CRS. This novel approach is also currently being investigated to be applied to different fields of interest. Epstein and colleagues (Aghajanian et al. 2019) demonstrated that engineered CAR-T cells can be exploited to reduce cardiac fibrosis and restore function in a mouse model of hypertensive heart failure. The authors speculated that engineered T cells could be used to target noncancer cells and investigated that cardiac fibroblasts, which contribute to fibrosis following heart injury, could be effectively targeted by CAR-T cells. These results provide proof of concept for the possibility of treating cardiac fibrosis with engineered T cells.

1.5 Inflammation at the Crossroad Between Cancer and Cardiovascular Diseases In cancer, inflammation plays a dual role. On the one hand, it has antitumorigenic function through the recognition and destruction of cancer cells; on the other hand, it predisposes to the development of cancer and promotes all stages of tumorigenesis, from initiation and promotion to invasion and metastasis (Galdiero et al. 2013). Recent evidence emphasized the involvement of several inflammatory mediators in the EMT (epithelial to mesenchymal transition), which is a crucial step toward tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties (Chaffer and Weinberg 2011; Libby and Kobold 2019). Tumor-associated inflammation can be induced at different time points of tumor development. It can precede carcinogenesis in the form of autoimmunity or infection, can be hampered by malignant cells, or can be induced by anticancer therapy (Mantovani et al. 2008). In this way, novel strategies have emerged in the last decades to modulate inflammation in order to achieve therapeutic anticancer immune responses. Visseren and colleagues of the UCC-SMART study group suggest that there is evidence that low-grade inflammation is also related to a higher risk of cancer (Van’t Klooster et al. 2019). The authors reported that chronic systemic low-grade inflammation, measured by CRP levels 60 ms are the cutoff of concern since, beyond these values, the risk of torsade de point increases significantly (Priori et al. 2015). Finally, conduction abnormalities such as

5.1 Introduction 69

complete bundle branch block require adjustment of the measured QT (e.g. subtracting the exceeding QRS duration due to intraventricular conduction delay from measured QT). This substraction is done before applying the formula chosen for correction or, alternatively, a different cutoff level (e.g., 550 ms) can be used (Porta-Sánchez et al. 2017; Bogossian et al. 2020). Regardless of the suspected etiology of the arrhythmia, electrolytes, full blood count, and thyroid function should always be tested (Zamorano et al. 2016; Lopez Fernandez and Van der Meer 2019). Echocardiogram is warranted to assess eventual structural disease (Zamorano et al. 2016; Brugada et al. 2019; Lopez Fernandez and Van der Meer 2019; Hindricks et al. 2020). Further specific investigations are necessary in case of arrhythmias encountered in peculiar clinical scenarios. For example, when myocarditis is suspected, cardiac MRI, and, in second instance, endomyocardial biopsy, can improve diagnostic power (Zamorano et al. 2016). Coronary-CT, SPECT, functional MRI, and invasive coronary angiography allow to detect CAD. With this regard, it should always be remembered that radiotherapy exposure, especially at younger age and high doses, is associated with proximal coronary involvement increasing the risk of large myocardial infarctions. Therefore, a lower threshold for invasive investigations in patients deemed at risk is reasonable (Hu et al. 2013). 5.1.4 Clinical Characteristics Several kinds of arrhythmias can be observed in patients with cancer. As in the general population, atrial fibrillation is the most common cause of concern. While the pro-arrhythmic effect of older chemotherapeutics (e.g., anthracyclines) is well known, the widespread use of newer compounds (e.g., TKI, immunomodulators, etc.) has increased the clinical scenario complexity. For example, evaluation for atrial fibrillation occurrence in patient treated with ibrutinib requires close collaboration between hematologist and cardiologist. Moreover, it should be considered that some arrhythmias are associated with combination of different drugs rather than with a single agent and that often they are facilitated by electrolyte derangements (sometimes caused by the same drug or concomitant agent used). In the subsequent table, we provide a list of chemotherapy drugs used in clinical practice and the arrhythmias they are more frequently associated with. 5.1.5 Treatment Treatment of chemotherapy side effects, including arrhythmic complications, often represents a hard clinical challenge. As in other field of oncology,

CDK4/6 inhibitors mTOR inhibitors

HDAC inhibitors

Proteasome inhibitors

Endogenous molecule

Platinum-based drugs Immunomodulatory drugs

Antifolate Microtubule agents

Antimetabolites

Therapy Class Inorganic compound Alkylating agent

Agent Arsenic trioxide Anthracyclinesa Amsacrine Cyclophosphamide Ifosfamide Melphalan 5-FU Capecitabine Cytarabinec Fludarabine Pentostatinc Gemcitabine Clofarabine Methotrexate Paclitaxele Docetaxelc Vincristinec Cisplatinf Lenalidomide Thalidomide Interleukin-2 Interferon-alfa Bortezomib Carfilzomibg Romidepsin Panobinostat Vorinostat Ribociclib Everolimus ++

cr cr + cr cr

+ cr cr + ++ + +

+ +++d

+ + +++ + ++ cr

AF ++ +++

++ cr

+ + + cr

+

+ cr +/+ cr

++

+ ++ cr cr

SVT ++ ++ +

cr cr

+ cr

+ cr +++ +

+++

cr

cr cr

+ cr

+

+ +

cr cr

+++ ++ cr cr

cr

AV Block +

crc +

Bradycardia + +

++ ++ ++ ++

cr

cr

cr +++

QTc prolongation +++ ++b +

+ cr cr

cr

cr cr

TdP ++

++ cr

+ cr cr + + cr

+/+

cr

VT/VF + + + cr + cr ++ +

cr cr cr +/cr + + cr cr

cr cr

cr

++ +

cr

SCD + + +

70 Cancer Therapy-Induced Arrhythmias

Kinase inhibitors

Therapy Class Monoclonal antibodies

Agent Alemtuzumab Cetuximab Necitumumab Pertuzumab Rituximab Trastuzumab Osimertinib Lapatinib Lenvatinib Pazopanib Sorafenib Sunitinib Vandetanib Bosutinib Dasatinib Imatinib Nilotinib Ponatinib Ibrutinibi Zanubrutinib Alectinib Ceritinib Crizotinib Brigatinib Lorlatinib Encorafenib Vemurafenib Gilteritinib Trametinib Ruxolitinib Selpercatinib ++

+ + ++ ++ +++ +

+ cr

+

+ + ++

AF ++ +

+

+ +

+ +

+

+ + + ++

SVT

++ +

+

+++ + +++ ++

++ +

+

+++ + +

+ + +

Bradycardia ++ +

+

++ +

+

+

AV Block

+ +++ ++ ++ + +

+ ++ +

++ +

++ + ++ ++ + + +++ ++ +

+

QTc prolongation

+

+ +

+

TdP

+ +

+

+

+ + +

VT/VF + +

+

+

+

cr +

cr

SCD + + ++ + +h cr h

5.1 Introduction 71

Agent Ipilimumab Nivolumab Pembrolizumab Tisagenlecleucel

AF + + + ++ ++

SVT

Bradycardia + + +

AV Block + + +

QTc prolongation TdP

VT/VF + + +

SCD + + +

a) Arrhythmic toxicity, contrary to cardiomyopathy, seems to be dose-independent (Buza et al. 2017). b) QT dispersion can be reduced by dexrazoxane (Galetta et al. 2005). c) Evidence limited to case report. d) If combined with cytarabine. e) Associated also with right and left bundle branch block (Kamineni et al. 2003). f) Risk of AF arises significantly if used for intrapericardial instillation or hyperthermic abdominal lavage (Tomkowski et al. 1997; Richards et al. 2006; Dhesi et al. 2013). g) The most part of cardiac adverse effect occurred during the first cycles and frequency did not increase after (Siegel et al. 2013). h) SCD could possibly be related to severe hypomagnesemia (Buza et al. 2017). i) Ibrutinib is associated with enhanced risk of major bleeding too, and appropriate anticoagulation therapy can be challenging (Lipsky et al. 2015).

CAR-T cell therapy

Therapy Class Immune checkpoint inhibitors

72 Cancer Therapy-Induced Arrhythmias

5.1 Introduction 73

the inherent difficulty is to balance prevention of unacceptable side effects avoiding interruptions of potential life-saving therapies. Close collaboration between cardiologists and oncologists is of paramount importance to deliver the best of care. 5.1.5.1 Atrial fibrillation Oversimplifying, atrial fibrillation treatment can be reduced to two main cornerstones: symptoms improvement and stroke prevention. • Symptoms improvement There is no compelling evidence of a significant difference in terms of mortality between a rhythm control and rate control strategy in patients with atrial fibrillation (Hindricks et al. 2020). The recent EAST – AFNET 4 trial showed that early initiation of rhythm-control therapy may convey clinical benefit in patients with recently diagnosed atrial fibrillation (Kirchhof et al. 2020). Active cancer or history of neoplasm were not among the exclusion criteria of the trial, but patients with any disease limiting life expectancy to less than 1 year could not be enrolled. Therefore, it is not clear whether the results of EAST – AFNET 4 trial can be extended to all patients with cancer developing atrial fibrillation and further investigations are warranted. The choice between rate and rhythm control should be mainly based on the aim of improving quality of life. Although this choice should follow usual considerations even in patients with cancer, two specific concerns should be taken into account. First, rhythm control can be more difficult to achieve since cancer itself, predisposing to development of atrial fibrillation, represents a non-removable potent arrhythmogenic factor. Thus, rate control is generally easier to achieve and favored over rhythm control (Lopez Fernandez and Van der Meer 2019; Hindricks et al. 2020). On the other hand, in selected patient (e.g., extremely symptomatic or with hemodynamic compromise) may be advisable to pursue rhythm control preventing atrial fibrillation from maintaining itself. Together with clinical judgment, patient’s involvement play a central role in the decisional process. It is worth to remind that obtaining information about potential underlying structural and/or valvular heart disease is of paramount importance, especially in oncological patients, before initiating antiarrhythmic drugs or performing invasive procedures. Whenever rate control is the strategy of choice, it seems reasonable to maintain heart rate below 110 bpm at rest although no specific target has been defined yet. The RACE II study compared lenient rate control (resting heart rate < 110 bpm) vs. strict rate control (target resting heart

74 Cancer Therapy-Induced Arrhythmias rate 60 ms, but some exceptions exist such as nilotinib, with an upper QTc cutoff of 480 ms) daily monitoring is warranted. Discontinuation of co-administered drugs with known QTc prolonging effects (such as anti-emetics, antibiotics, and others that can be found at www.crediblemeds.org) and electrolytes correction are the first therapeutic measures to adopt. Bradycardia should also be corrected, if necessary, with temporary pacing. Offending chemotherapeutic drug should be temporally suspended and resumed once QTc normalizes, at reduced dose if indicated. Balancing potential side effects of chemotherapeutics is essential; given the high lethality of some malignancies, benefits of the drugs could outweigh risk of QTc prolongation. In these cases, monitoring should be even closer. If torsades de points or similar arrhythmias develop (and also after a spontaneous resolution, until the cause is not removed), magnesium

76 Cancer Therapy-Induced Arrhythmias sulfate should be administered. Isoprenaline can be useful to increase heart rate and to reduce the period of susceptibility to major ventricular arrhythmias in heart cycle, but it is associated with an arrhythmogenic effect. A similar effect can be obtained by placing a temporary transvenous pacemaker or with re-programming of a pre-existing definitive pacemaker/implantable cardioverter defibrillator to a lower rate limit ≥90 bpm (Priori et al. 2015; Zamorano et al. 2016). 5.1.5.3 AV conduction disturbances and sinus node dysfunction As mentioned before, taxanes are the drugs most frequently associated with bradycardia which is well tolerated and asymptomatic in the vast majority of cases (Lopez Fernandez and Van der Meer 2019). An attempt to remove causative factors (including comedications with negative chronotropic effect) remains the best strategy. If not feasible, pacemaker implantation (temporary or definitive) is the treatment of choice (Zamorano et al. 2016). 5.1.5.4 Supraventricular arrhythmias With the exception of atrial fibrillation, as discussed above, treatment of supraventricular arrhythmias does not differ from non-oncological patients (Zamorano et al. 2016). The majority of supraventricular arrhythmias are easily managed with a high percentage of success, but the feasibility and net clinical benefit of invasive treatments (i.e., transcatheter ablation) need to be carefully weighted in such a frail population. 5.1.5.5 Ventricular arrhythmias Acute management of ventricular arrhythmias is beyond the scope of Chapter V. QTc interval prolongation has been discussed above. In oncological patients, ventricular arrhythmias may be a direct effect of cardiotoxic drugs and/or radiotherapy or an indirect manifestation of induced ischemia or electrolyte derangements. Predisposing factors should be removed whenever possible; discontinuation of chemotherapeutics should always be carefully weighted taking into account the clinical condition of each patient and the severity of the arrhythmias. Indeed, grade 4 complications (i.e., lifethreatening) preclude further use of the offending drugs. 5.1.6. Prophylaxis As in the general population, also in patients with cancer prevention of arrythmias should start from cardiovascular risk factors control. Every effort to avoid the development of structural heart disease should be implemented.

5.1 Introduction 77

The possibility to predict which patient will experience a reduction of left ventricular function (with or without heart failure symptoms) remains an ambitious aim. The echocardiographic assessment of global longitudinal strain (GLS) and serial measurements of biomarkers such as natriuretic peptides (i.e., BNP/NTproBNP) seem promising, but no strong recommendations on their routine use can be provided (Zamorano et al. 2016). Hypertension, occurring in one out of three patients with cancer, is the commonest cardiovascular comorbidity encountered in clinical practice. Rarely, hypertension can predict and indicate the efficacy of therapies targeting angiogenesis, but, even in those circumstances, it has to be promptly treated. Treatment of hypertension may represent the single most effective preventive action for the entire spectrum of cardiac arrhythmias occurring in patients with cancer (Lopez Fernandez and Van der Meer 2019). General rules for prevention of coronary artery disease apply also in patients with cancer. Healthy diet, smoking cessation, regular exercise, and weight control can prevent coronary artery disease and seem also effective in improving quality of life and mitigating cardiotoxicity (Zamorano et al. 2016). Electrolyte derangements have been already discussed before. Prevention of this common clinical problem, often with simple expedients such as hydration, can substantially reduce the risk of arrhythmias. Pharmacological prevention proved effective in reducing the risk of chemotherapy-induced cardiotoxicity. Candesartan showed a modest preventive effect on left ventricular ejection fraction reduction induced by anthracyclines, while perindopril, bisoprolol, and metoprolol failed to show significant effect. Betablockers showed instead a significative preventive effect in reducing the incidence of left ventricular systolic dysfunction and heart failure in patients receiving anthracyclines associated with trastuzumab. Pharmacological preventive strategies seem reasonable when troponin elevation is observed consequently to chemotherapy. Dexrazoxane is approved for the prevention of toxicity induced by doxorubicin and epirubicin when exceeding dose of 300 and 540 mg/m2, respectively (Zamorano et al. 2016). One of the most arrhythmogenic situations often encountered in cardio-oncology is surgery. Atrial fibrillation in this setting is particularly challenging. The role of perioperative beta blockade has been a matter of debate for years with recent studies recommending its use before cardiac surgery but not before non-cardiac surgery because an increased risk of death and stroke has been observed (Blessberger et al. 2018). Amiodarone has been proven effective in preventing the occurrence of atrial fibrillation after cardiac surgery, with an additive effect on beta-blockers (Auer et al. 2004). Data are currently insufficient to advise the use of other drugs.

78 Cancer Therapy-Induced Arrhythmias The adoption of techniques oriented to reduce dose absorption by the heart during radiotherapy is obviously beneficial. Modern techniques brought improvement in the prevention of actinic cardiomyopathy; however, irradiation of the heart remains unavoidable when targeting adjacent structures (Zamorano et al. 2016). In conclusion, prevention of cancer-related arrhythmias has been poorly investigated so far and many knowledge gaps still exist. Every effort should be made to allow patients with cancer to receive needed treatments without being limited by preventable complications.

References 1. Ajero PM, Belsky JL, Prawius HD, et al. Chemotherapy-induced hypocalcemia. Endocr Pract. 2010;16:284–90. 2. Arbuck SG, Strauss H, Rowinsky E, et al. A reassessment of cardiac toxicity associated with Taxol. J Natl Cancer Inst Monogr. 1993:117–30. 3. Auer J, Weber T, Berent R, et al.; Study of Prevention of Postoperative Atrial Fibrillation. A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial. Am Heart J. 2004;147:636–43. 4. Berardi R, Torniai M, Lenci E, et al. Electrolyte disorders in cancer patients: a systematic review. J Cancer Metastasis Treat 2019;5:79. 5. Bischiniotis TS, Lafaras CT, Platogiannis DN, et al. Intrapericardial cisplatin administration after pericardiocentesis in patients with lung adenocarcinoma and malignant cardiac tamponade. Hellenic J Cardiol. 2005;46:324–9. 6. Blessberger H, Kammler J, Domanovits H, et al. Perioperative betablockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2018;3:CD004476. 7. Bogossian H, Linz D, Heijman J, et al. QTc evaluation in patients with bundle branch block. Int J Cardiol Heart Vasc. 2020;30:100636. 8. Brell JM. Prolonged QTc interval in cancer therapeutic drug development: defining arrhythmic risk in malignancy. Prog Cardiovasc Dis. 2010;53:164–72. 9. Brugada J, Katritsis DG, Arbelo E, et al.; ESC Scientific Document Group. 2019 ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J. 2020;41:655–720.

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10. Buza V, Rajagopalan B, Curtis AB. Cancer Treatment-Induced Arrhythmias: Focus on Chemotherapy and Targeted Therapies. Circ Arrhythm Electrophysiol. 2017;10:e005443. 11. Chang HM, Okwuosa TM, Scarabelli T, et al. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2. J Am Coll Cardiol. 2017;70:2552–2565. 12. Chao TF, Liao JN, Tuan TC, et al. Incident Co-Morbidities in Patients with Atrial Fibrillation Initially with a CHA2DS2-VASc Score of 0 (Males) or 1 (Females): Implications for Reassessment of Stroke Risk in Initially ‘Low-Risk’ Patients. Thromb Haemost. 2019;119:1162–1170. 13. Dhesi S, Chu MP, Blevins G, et al. Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management. J Investig Med High Impact Case Rep. 2013;1:2324709613480346. 14. Farmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: atrial fibrillation in cancer. J Am Coll Cardiol. 2014;63:945–53. 15. Fuentes HE, Tafur AJ, Caprini JA. Cancer-associated thrombosis. Dis Mon. 2016;62:121–58. 16. Galetta F, Franzoni F, Cervetti G, et al. Effect of epirubicin-based chemotherapy and dexrazoxane supplementation on QT dispersion in nonHodgkin lymphoma patients. Biomed Pharmacother. 2005;59:541–4. 17. Giustozzi M, Ali H, Reboldi G, et al. Safety of catheter ablation of atrial fibrillation in cancer survivors. J Interv Card Electrophysiol. 2020. doi: 10.1007/s10840-020-00745-7. 18. Guglin M, Aljayeh M, Saiyad S, et al. Introducing a new entity: chemotherapy-induced arrhythmia. Europace. 2009;11:1579–86. 19. Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol. 2020;17:474–502. 20. Hindricks G, Potpara T, Dagres N, et al.; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42:373–498. 21. Hu YF, Liu CJ, Chang PM, et al. Incident thromboembolism and heart failure associated with new-onset atrial fibrillation in cancer patients. Int J Cardiol. 2013;165:355–7. 22. Kamineni P, Prakasa K, Hasan SP, et al. Cardiotoxicities of paclitaxel in African Americans. J Natl Med Assoc. 2004;96:995. 23. Kirchhof P, Camm AJ, Goette A, et al.; EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383:1305–1316

80 Cancer Therapy-Induced Arrhythmias 24. Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2015;100:1571–8 25. Lopez Fernandez T and Van der Meer P. Cardio-oncology: it is not only heart failure! e Journal of Cardiology Practice 2019; 16: 38. 26. Mir H, Alhussein M, Alrashidi S, et al. Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area. Can J Cardiol. 2018;34:1059–1068. 27. Muluneh B, Richardson DR, Hicks C, et al. Trials and Tribulations of Corrected QT Interval Monitoring in Oncology: Rationale for a PracticeChanging Standardized Approach. J Clin Oncol. 2019;37:2719–2721. 28. Naing A, Veasey-Rodrigues H, Hong DS, et al. Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs. Ann Oncol. 2012;23:2960–2963. 29. Natasha G, Chan M, Gue YX, et al. Fatal heart block from intentional yew tree (Taxus baccata) ingestion: a case report. Eur Heart J Case Rep. 2019;4:1–4. 30. Osuna PM, Udovcic M, Sharma MD. Hyperthyroidism and the Heart. Methodist Debakey Cardiovasc J. 2017;13:60–63. 31. Porta-Sánchez A, Gilbert C, Spears D, et al. Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review. J Am Heart Assoc. 2017;6:e007724. 32. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–8. 33. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al.; ESC Scientific Document Group. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2793–2867. 34. Richards WG, Zellos L, Bueno R, et al. Phase I to II study of pleurectomy/ decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J Clin Oncol. 2006;24:1561–7. 35. Sanz AP, Gómez JLZ. AF in Cancer Patients: A Different Need for Anticoagulation? Eur Cardiol. 2019;14:65–67

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6 Cancer in the Heart Failure Population Alessandra Cuomo, MD1; Flora Pirozzi, MD, PhD1; Francesca Paudice, MD1; Giovanni Perrotta, MD1; Giovanni D’Angelo, MD1; Antonio Carannante, MD1; Carlo Gabriele Tocchetti, MD, PhD, FHFA, FISC1,2,3; Valentina Mercurio, MD, PhD, FISC1; Pietro Ameri MD, PhD, FHFA4,5 Department of Translational Medical Sciences, Federico II University, Naples, Italy 2 Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy 3 Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy 4 Cardiovascular Disease Unit, IRCCS Italian Cardiovascular Network, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 5 Department of Internal Medicine, University of Genova, Genoa, Italy 1

*Correspondence to: Alessandra Cuomo, MD Dipartimento di Scienze Mediche Traslazionali Università degli Studi di Napoli Federico II Via Sergio Pansini, 5 80131 Naples, Italy Phone. +39-081-746-2242 Fax: +39-081-746-2246 Email: [email protected] KEYWORDS: Cancer; Cardiotoxicity; Cardiovascular Diseases;Heart Failure; Preventive Cardiology;

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84 Cancer in the Heart Failure Population

6.1 Introduction Along with the increase in life expectancy, the incidence of conditions associated with aging, such as cancer and cardiovascular diseases (CVDs), has also increased, and this trend is expected to persist over the next decade (Heidenreich et al. 2011). Heart failure (HF) represents the final stage of different CVDs and its incidence has notably grown during last decades (Ponikowski et al. 2016; Benjamin et al. 2018). Furthermore, it is common knowledge that cancer and cardiovascular diseases are responsible for most of non-accidental deaths in industrialized countries and listed among the leading causes of mortality in the world (Ameri et al. 2018; Anker et al. 2018). At first, Cardio-Oncology focused predominantly on the development of cardiac toxicity due to oncological treatments, such as anthracyclines, wellknown for their adverse cardiovascular effects,with several antineoplastic treatments being associated with cardiovascular side effects that may lead to new-onset HF (Zamorano et al. 2016; Armenian et al. 2017; Denlinger et al. 2018). Over the past decade, the field of cardio-oncology has been expanding, acquiring more importance in the management of cancer patients, considering the tight link between cancer and CVDs (Lenihan et al. 2016; Moslehi et al. 2019). Indeed, not only HF can be induced by cancer therapies, but recent research has pointed out that the presence of HF itself might promote tumorigenesis (de Boer et al. 2019). In this setting, the management of HF patients who develop cancer represents a challenge for cardio-oncologists (Aboumsallem et al. 2020), considering that little is known about standard of care of patients with pre-existing HF who develop malignancies. Furthermore, most trials on antineoplastic treatments exclude patients with HF because of their numerous comorbidities and worse prognosis, compared to the general population (Ameri et al. 2018). Aim of Chapter VI is to discuss the epidemiology of new-onset cancer in the HF population, the pathophysiological link between those two diseases and to explore possible clinical implication for practitioners. Figure 6.1 summarizes the links between HF and cancer, by means of epidemiology, phatophysiology and clinical implications.

6.2 Heart Failure and New Onset Cancer: Epidemiology The progressive aging of world population predisposes to an increased incidence of HF, which represents a primary cause of morbidity and mortality in the world, due to age-related cardiac structure alteration. Moreover, the

6.2 Heart Failure and New Onset Cancer: Epidemiology 85

Figure 6.1 Graphic summary of the link between heart failure and cancer

improved treatments of cardiovascular diseases (e.g., acute myocardial infarction, AMI), leading to significant reduction in short-term mortality from these causes, did not affect cardiac remodeling and subsequent development of HF (Hasin et al. 2013; Ameri et al. 2018). Surprisingly, higher mortality and morbidity among HF patients, compared to general population, are more frequently attributed to non-cardiovascular causes than cardiovascular ones (Hasin et al. 2013). Cancer is another major cause of mortality and its incidence increases with age as well (Hasin et al. 2017). Albeit HF and cancer have been considered as distinguished conditions for a long time, recent evidence shows that they are related and may be considered as comorbidities (Brancaccio et al. 2020). It is wellknown that the use of cardiotoxic oncologic therapies can determine cardiac damages which ultimately may lead to HF (Zamorano et al. 2016).

86 Cancer in the Heart Failure Population Besides, the tumor itself can stimulate myocardial dysfunction through systemic alterations (Hasin et al. 2016). Interestingly, some epidemiological and experimental studies have proved that exists a greater risk of cancer development in patients with pre-existing diagnosis of HF (Hasin et al. 2013, 2016, 2017; Banke et al. 2016). A case-control study explored cancer history among subjects with a new diagnosis of HF (cases) and without HF (controls), finding no association between cancer diagnosis and succeeding development of HF. Then, in a cohort study, the authors examined the long-term risk of developing cancer among HF patients compared to controls, excluding subjects with a prior diagnosis of malignancies, and adjusting for major shared risk factors (e.g., body mass index, smoking, diabetes mellitus, and hypertension). The results showed a 60% increased risk of incident cancer in HF patients, with no sex differences in the association but a 56% higher risk of death in HF patients who developed cancer compared to HF patients who did not (Hasin et al. 2013). In a different prospective cohort study, the same group , investigated the risk of cancer in subjects surviving first acute myocardial infarction (AMI) comparing patients who developed HF after AMI to those who did not develop it. HF patients had a 71% greater risk of later cancer diagnosis. Since these groups had history of AMI, both shared many risk factors and medications (post-AMI treatment); therefore, this study, removing these variables, offers an even stronger evidence of the association between HF (especially with reduced ejection fraction, HFrEF) and cancer (Hasin et al. 2016). Another cohort study explored the incidence of all types of cancer in a group of Danish patients with HF compared with the general population, and they observed, adjusting for shared risk factors, higher risk of all major types of tumors, except for prostate neoplasms, in HF patients. This study also reported increased mortality among HF patients with new-onset cancer than oncological patients without HF (Banke et al. 2016). However, it is important to consider that the association between HF and cancer found in these studies can be partially explained by surveillance bias. Patients enrolled in these studies undergo an active follow-up with regular visits and diagnostic tests that may reveal cancer earlier than in general population (e.g., chest X-ray evidence a lung lesion) or discover tumors that would have not been discovered otherwise (Ameri et al. 2018). Furthermore, typical medications used for HF treatment may reveal malignancies that would have been otherwise asymptomatic: for example, the use of anticoagulant and antiplatelets could determine bleeding in patients with unrevealed gastrointestinal neoplasm. Conversely, many symptoms can

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manifest themselves both in HF and cancer (e.g., dyspnea, fatigue, weight loss, etc.) and could be considered as caused by the advancing of HF rather than the presence of new-onset malignancies, delaying cancer diagnosis (Ameri et al. 2018). Over the past decade, major improvements in cardiovascular care have led to a significant reduction of the number of deaths due to cardiovascular causes. Consequently, HF patients, whose life expectancy has grown compared to the past, might develop other comorbidities, especially cancer. In a recent paper, Dr. Tini et al. (2020) demonstrated that cancer is among the most frequent causes of death in patients with HFrEF. In particular, the authors, performing a meta-analysis on phase 3 randomized controlled trials enrolling patients with HF, found that cancer mortality was not influenced by treatment contrary to what happened for cardiovascular mortality (Tini et al. 2020). Moreover, a subanalysis of the population enrolled in the GISSI-HF trial showed that 3.7% of patients in the trial presented cancer at enrollment and the presence of malignancies increased the risk of death by all causes, after adjusting for age and confounders. Furthermore, among patients who did not present cancer at enrollment, 10.4% died of cancer during follow-up. Finally, patients with cancer-related deaths presented worse NYHA functional class, higher systolic cardiac function, were administered with lower doses of diuretics, showed lower levels of creatinine and uric acid but higher concentrations of cholesterol and hemoglobin, and were characterized by shortened history of HF and better cardiac systolic function (Ameri et al. 2020). Intriguingly, these findings suggest that cancer-related death in the HF population is independent by the severity of HF itself, confirming the hypothesis that cancer significantly worsens HF prognosis (Ameri et al. 2020). These discoveries suggest the importance of a holistic approach to HF patients and the need to enhance knowledge on the pathophysiological mechanisms underlying the association between HF and cancer in order to define new standards of care for these patients.

6.3 Mechanisms of Cancer Development in the Heart Failure Population Over the past decades, research has been focusing on unraveling the possible link between cancer and cardiovascular diseases, especially HF. First of all, malignancies and HF share common risk factors like smoking, aging, and metabolic syndrome (MetS) and its components, such as insulin resistance and obesity (de Boer et al. 2019). Furthermore, several mechanisms

88 Cancer in the Heart Failure Population underlying HF development and persistence are involved in carcinogenesis and cancer spread, including the low-grade inflammatory state typical of HF which may represent a substrate for cancer development in the HF population (van’t Klooster et al. 2019). The presence of MetS, based on the co-existence of at least three conditions among increased fasting glucose, dyslipidemia, central obesity, and systemic hypertension, is itself an important risk factor for the development of cardiovascular diseases (Eckel et al. 2005). Moreover, dyslipidemia seems associated with increased risk of developing colon-rectal cancers (Yao and Tian 2015), while hyperglycemia has been related with higher risk of pancreas, endometrium, and urinary tract cancers, and of malignant melanoma (Stattin et al. 2007). On the other hand, obesity has been associated with increased risk of carcinogenesis (Lauby-Secretan et al. 2016), higher rate of cancer recurrence and recrudescence (Ecker et al. 2019), and worse prognosis in patients already diagnosed with malignancies (Pajares et al. 2013). Aging itself is characterized by the presence of oxidative stress and cellular senescence, both part of degenerative mechanisms already linked to the development of both cancer and cardiovascular diseases (Abete et al. 1999; Olinski et al. 2007; Liguori et al. 2018; Liberale et al. 2020). Tobacco use is also an important risk factor for the development of several cardiovascular diseases, such as stroke (Boehme et al. 2017) and systemic hypertension (Virdis et al. 2010), and it has been recognized as an independent risk factor for the development of acute coronary artery disease (Benjamin et al. 2018). On the other hand, tobacco use is well known for its carcinogenic potential and it is recognized as one of the main causes of mortality due to malignancies. In particular, almost 4% of all malignancies in women and 25% in men seem to be smoke-related, while, considering both sexes together, 16% of cancers in industrialized countries and 10% in less developed countries might be attributable to tobacco use (Sasco et al. 2004). However, as mentioned above, there are other pathways that seem to be involved in both HF and cancer, besides common risk factors. For instance, the renin-angiotensin-aldosterone system (RAAS), the hyperactivation of the sympathetic nervous system (SNS), and the natriuretic peptide system are not only considered as HF hallmarks, but it has also been speculated that they might be associated with increased risk of developing cancer (Sakamoto et al. 2017; Bertero et al. 2019). Indeed, the activation of the RAAS has been proven to be strongly related to cancer spread and neoangiogenesis, through increased expression of angiogenic factors, contributing altogether to worsen cancer prognosis (George et al. 2010). Considering this plausible link between RAAS and malignancies, over the past decade, researches

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have explored whether RAAS blockers might play a role as antineoplastic drugs, but the results are still controversial (Sipahi et al. 2010; Wang et al. 2013). Intriguingly, in a large meta-analysis, RAAS blockers proved to be effective on all cancer-related endpoints (Sun et al. 2017). A positive correlation between the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) and cancer risk has been explored, based on the results from the CHARM (Candesartan in Heart Failure: Assessment of Mortality and Morbidity) trial (Pfeffer et al. 2003) and SOLVD (Studies of Left Ventricular Dysfunction) trial. In particular, in the CHARM trial, on candesartan versus placebo, more patients died from cancer in the candesartan group, despite the incidence of non-fatal cancer being similar between both groups (Pfeffer et al. 2003). In the SOLVD trial, on enalapril versus placebo, 43 patients in the enalapril group and 41 patients in the placebo group developed cancer, mostly affecting the gastrointestinal tract, the liver, gallbladder, or pancreas (SOLVD Investigators et al. 1992). Nevertheless, there might be an important bias to be considered: HF patients receiving life-saving therapies and enrolled in large studies like the CHARM and the SOLVD are admitted more often for outpatient follow-ups and this might contribute to diagnose malignancies that might have gone undiagnosed in the real world (Ameri et al. 2018). It has also been demonstrated that the angiotensin II pathway has a pivotal role in both angiogenesis via VEGF pathway and carcinogenesis, including cell proliferation and migration. Intriguingly, recent data suggest that angiotensin inhibitors might be included in some antineoplastic protocols for metastatic renal cell carcinoma (McDermott et al. 2015) or might play a relevant role in the neoadjuvant therapy of locally advanced pancreatic cancer in association with FOLFIRINOX, the actual standard of care (Murphy et al. 2019). Considering the SNS, it is well known that β-adrenergic receptors (βARs) have a central role in HF developing, and their role has been investigated also in other diseases, including tumorigenesis. In particular, it has been hypostasized that βARs hyperactivation may favor carcinogenesis, via the β-arrestin 1 pathway (Hara et al. 2011), and may be involved in cellular proliferation, through the activation of CREB, NF-kB, and AP-1 (Zhang et al. 2010). Furthermore, it seems that the bARs pathway plays an important role in cellular apoptosis, leading to tumor cells resistance through the activation of different mechanisms, such as the inhibition of proapoptotic protein BAD (Hassan et al. 2013), gene suppressor p53 (Zhang et al. 2010), and anoikis (Sood et al. 2010). Intriguingly, both β1 and β2 adrenergic receptors are widely expressed in all solid cancer cells, suggesting that they might play an important role in

90 Cancer in the Heart Failure Population malignancies development and tumor cells survival, besides their well-studied and pivotal role in heart function (Barron et al. 2011; Coelho et al. 2017). These data support the hypothesis that β-blockers in cancer patients might be used not only for their cardio-protective effects against cardiotoxicity induced by antineoplastic drugs but also adjuvant drugs in oncological protocols (Sysa-Shah et al. 2016; Avila et al. 2018; Guglin et al. 2019). Results from different studies suggest that the SNS might also contribute to the establishment of the microenvironment which favors cancer development and growth (Cole et al. 2015). In particular, βARs activation enhances the production of prostaglandin E2 and VEGF-C by tumor-associated macrophages (Galdiero et al. 2013), which ultimately lead to increased density of both lymphoid and blood vessels peri- and intra-neoplastic, favorizing tumor spread and metastasis (Armaiz-Pena et al. 2015). Finally, βARs seem to be able to suppress the natural killer cells activity, creating an environment favorable for cancer development and dissemination (Shakhar and Ben-Eliyahu 1998). As stated above, natriuretic peptides also seem to be involved in carcinogenesis, and their role has been recently explored (Kong et al. 2008; Nojiri et al. 2015). It is well known that natriuretic peptides, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and its inactive N-terminal portion (NT-proBNP) not only increase during HF but also have a pivotal pathophysiological role (Wong et al. 2017). Interestingly, recent data suggest that the presence of circulating natriuretic peptides, i.e., NT-proBNP, might be involved in tumor progression and severity. These findings also support the hypothesis that the cancer patients may present subclinical morphological or functional heart damage, opening the road to the possible use of HF medications in oncological patients as part of the anticancer protocols, beyond their cardioprotective role against cardiotoxicity induced by chemotherapy (Pavo et al. 2015). The presence of a mild chronic inflammatory state distinguishes both HF and cancer. Over the past century, the link between inflammation and cancer (Lesterhuis et al. 2011) and the inflammatory state and cardiovascular diseases (van’t Klooster et al. 2019) has been extensively explored. Indeed, it has been demonstrated that inflammation plays a pivotal role in the establishment and advancement of the atherosclerotic process (Libby et al. 2019), promoting thrombosis and ultimately leading to the development of ischemic heart disease (Koene et al. 2016). Furthermore, data suggest that HF patients present increased plasma concentrations of pro-inflammatory cytokines (Levine et al. 1990; Testa et al. 1996; Torre-Amione et al. 1996),

6.4 Cancer in Heart Failure Patients: Clinical Implications 91

compatible with the mild chronic inflammatory state that characterizes these patients (Suthahar et al. 2017). It has also been demonstrated that cells post-myocardial infarction present an intense response to stress, characterized by the activation of NF-kB (Hasin et al. 2013), known to be one of the major promoters of cancer development and growth, leading to the activation of numerous genes involved in different tumor mechanisms, such as cell proliferation, survival, spreading, and angiogenesis (Chaturvedi et al. 2011; Meijers and De Boer 2019). Concerning pro-inflammatory cytokines, interleukin-1 (IL-1) seems to play a central role in both cardiovascular diseases and cancer. In particular, the Canakinumab Anti-Inflammatory Thrombosis Outcome (CANTOS) trial demonstrated that canakinumab, an antibody targeting IL-1β, was able to reduce the incidence of major cardiovascular events in patients with clinical history of myocardial infarction (Ridker et al. 2017a) and also showed to be effective in reducing the incidence of lung cancer in this setting (Ridker et al. 2017b). To further support the hypothesis that HF itself is able to promote carcinogenesis, an elegant work from Meijers and colleagues (2018) showed that the failing heart releases factors which promote cancer growth, independently from the hemodynamic impairment (Meijers et al. 2018). Moreover, Meijers et al. demonstrated that plasma samples from 101 patients with chronic HF present increased levels of five proteins, compared to 180 healthy patients (Hillege et al. 2001; Schroten et al. 2013) Finally, it was also demonstrated that HF biomarkers and proteins related to inflammation were able to predict the incidence of cancer, independently from the tumor risk factor (Kitsis et al. 2018).

6.4 Cancer in Heart Failure Patients: Clinical Implications The co-existence of cancer and cardiovascular diseases always represents a challenge for clinicians. For instance, cardio-oncology first aimed at treating cardiotoxicity and HF induced by antineoplastic treatments. Nowadays, physicians not only have to deal with the cardiovascular effects of oncological treatments but also have to relate to HF patients who develop new-onset cancer and need to be treated for both diseases. Indeed, new-onset cancer may present with symptoms that may overlap with those of the preexisting HF. Furthermore, the presence of new-onset cancer in HF patients worsens the already poor prognosis of these patients and clinicians need to be particularly careful when deciding the optimal treatments for both diseases (Ameri et al. 2018).

92 Cancer in the Heart Failure Population Physicians need to be aware that there are numerous clinical implications in this setting: in HF patients, the presence of new-onset cancer impairs the already fragile homeostasis, and it may also increase the risk of developing cardiotoxicity induced by anticancer treatments and can be a burden to both cardiological and oncological therapeutic approaches, leading to a poorer prognosis in this subset of patients. Additionally, new-onset cancer itself may contribute to further compromise heart function (Musolino et al. 2019), for example, inducing electrolytes or hormonal alterations, deteriorating the already compromised endothelium or worsening the chronic inflammation state (Ameri et al. 2018). A tight collaboration between cardiologists and oncologists is fundamental to ensure the best assistance to all patients with pre-existing HF who develop new-onset cancer. Cardiologists and HF specialists need to perform a comprehensive evaluation of HF patients, not only to diagnose possible newonset cancers but also to fully assess patients’ characteristics. In particular, it is highly suggested to perform a full baseline evaluation, including clinical and family history, physical examination, ECG, blood withdrawal (in order to verify electrolyte status, exclude the presence of anemia, newonset diabetes, or hormonal alterations), echocardiography, and other tests that are considered necessary by the clinician according to each patient’s condition. Moreover, it is essential to perform a risk/benefit analysis for each subject and evaluate all the possible therapeutic options for both HF and cancer in order to choose the best possible treatment management, tailored to each patient’s specific needs (Ameri et al. 2018; Lancellotti et al. 2018; Pareek et al. 2018). To provide the best clinical care, the clinician should first address the modifiable comorbidities (i.e., suggest weight loss, when necessary, and smoking cessation) and optimize cardiac therapy, including up-titration of β-blockers, ACEi, ARBs, neprilysin inhibitors, and diuretics and optimization of anti-diabetes medications (Ponikowski et al. 2016; Ameri et al. 2018). Patients should also be evaluated for the presence of pre-existing valvular defects and residual ischemia, addressing these issues when needed. Moreover, it is fundamental to promptly address any hormonal, metabolic, or electrolytes disorder, considering that their persistence may increase patients’ risk of developing cardiovascular toxicities induced by oncological treatments (Zamorano et al. 2016; Armenian et al. 2017; Ameri et al. 2018; Denlinger et al. 2018). Unfortunately, optimization and up-titration of HF specific treatment may be a long process, sometimes requiring months, which could delay the start of oncological treatments, both surgical and chemotherapy, further compromising patients’ prognosis (Ameri et al. 2018). For example, patients

6.4 Cancer in Heart Failure Patients: Clinical Implications 93

may require a coronary angioplasty before oncological treatments initiation, leading to the administration of double antiplatelet therapy (DAPT) for at least a month after the angioplasty that can postpone cancer surgery due to the increased risk of bleeding induced by the cardiological treatment. Obviously, physicians need to perform a careful evaluation of the bleeding risk induced by the DAPT on one side and, on the other side, of the risk of intra-stent thrombosis associated with the DAPT suspension (Valgimigli et al., 2018; Neumann et al. 2019). Clinicians should schedule regular follow-ups for HF-cancer patients to promptly identify any signs or symptoms of clinical worsening, which may be the manifestation of new-onset cardiotoxicity, and to intervene immediately in case of serum alteration or any other signs of decompensate HF. Most importantly, the clinician should recommend withdrawal from oncological treatments only when strictly necessary in order to guarantee to as many HF patients as possible to complete the antineoplastic protocols needed. Furthermore, cardiologists who treat HF patients who develop cancer need to be fully aware of the fragility of these patients. Hasin and colleagues showed that HF patients who develop cancer are characterized by worse prognosis when compared to patients without HF (Hasin et al. 2013). However, as the authors themselves explain, this data might be related to higher prevalence of comorbidities in the HF population and by the increased mortality risk due to the co-existence of HF and cancer (Mamas et al. 2017). Additionally, HF patients with malignancies present higher risk of hospitalization, which further compromise their prognosis, increasing the mortality risk (Omersa et al. 2016). As described above, Banke and colleagues explore the incidence of new-onset cancer in the HF population comparing data with the Denmark general background population. In their study, the authors stratified their sample into three subgroups according to age: patients 70 years old. The subanalysis showed that HF patients 70 years old, respectively (Banke et al. 2016). These findings are consistent with the hypothesis that death risk of pre-existing HF overlays is derived by new-onset malignancies, contributing to worsen patients’ outcomes. On the other hand, pre-existing HF and new-onset cancer might be linked by common symptoms, and cancer can further impair the already precarious homeostasis of HF patients (Ameri et al. 2018; Musolino et al. 2019). Another important issue to be addressed when dealing with both HF patients and cancer patients is the psychological burden, considering that

94 Cancer in the Heart Failure Population both diseases are associated with depression, which can further negatively impact prognosis (Newhouse and Jiang 2014; Sotelo et al. 2014). Obviously, the psychological impact of the new-onset cancer diagnosis in a patient that is already facing progressive chronic diseases, such as pre-existing HF, can additionally worsen patients’ mental status. Physicians that treat HF patients need also to be aware of the complexity of antineoplastic protocols of cancer patients. In particular, HF patients with new-onset malignancies present higher risk of developing cardiovascular toxicities due to the oncological treatments (Zamorano et al. 2016; Armenian et al. 2017; Ameri et al. 2018; Denlinger et al. 2018). Another issue to be dealt with is the higher perioperative mortality risk of patients with pre-existing HF that can develop cancer that can limit oncological treatments and further worsen prognosis (Smit-Fun and Buhre 2016; Kravchenko et al. 2015). Another important issue to be faced is the management of fluids during chemotherapy administration. Indeed, many antineoplastic treatments present renal toxicity among their adverse effects and, for this reason, are administered with large amount of fluids to be diluted (Cosmai et al. 2016). Needless to underline that HF patients often cannot be administered with as many fluids as standard patients, considering the risk of fluids overload. On the other hand, HF patients often present chronic kidney failure among their comorbidities, thus increasing the risk of renal toxicity due to anticancer treatments (Schefold et al. 2016). To reduce the risk of renal impairment, fluid doses should be reduced in HF patients, while the time of infusion could be prolonged, and diuretic therapy should be tailored to patient’s need, for example, increased when large amount of fluids have to be administered, to avoid pulmonary edema and other manifestations of fluids overload (Ponikowski et al. 2016; Ameri et al. 2018). Cancer itself is also a predisposing factor for arrhythmias, such as QT prolongation and atrial fibrillation (AFib; Farmakis et al. 2014), which has been related to increased mortality risk in the HF population (Mamas et al. 2009). Although the pathophysiological mechanisms are not quite understood, it seems that AFib in cancer patients might be due to thoracic surgery, advanced age, metabolic or electrolyte impairment, and hypoxia (Farmakis et al. 2014). Recent data suggest that oral anticoagulants are superior to warfarin, thanks to their safety profile and less drug−drug interaction (Park and Khorana 2019). Indeed, it is fundamental to periodically interrogate patients’ electronic devices when present, such as pacemakers and implantable defibrillators. High attention should be paid to patients who undergo radiotherapy, considering that radiation may impair the functionality of such electronic devices (Viganego et al. 2016).

6.4 Cancer in Heart Failure Patients: Clinical Implications 95

When dealing with HF-cancer patients, clinicians need to remember that cancer itself might have both pro-hemorrhagic and prothrombosis effects, according to tumor characteristics, and the management of DAPT and anticoagulation treatment has to be tailored on each specific case. For example, the presence gastrointestinal malignancies or central nervous system metastasis are associated with higher risk of major bleeding and anticoagulation treatment should be avoided, when possible (Angelini et al. 2019). For example, in patients with Afib and colon-rectal tumors, left atrium appendage occlusion might be considered to avoid the bleeding risk associated with anticoagulation treatment in this peculiar subset of patients (Meier et al. 2014; Glikson et al. 2020; Hindricks et al. 2020). On the other hand, thrombotic diathesis is a common feature in cancer patients who, thus, are more likely to develop deep vein thrombosis, pulmonary embolisms, and central venous catheter thrombosis (Park and Khorana 2019). Hence, a correct bleeding/thrombosis risk stratification is pivotal in HF patients who develop cancer in order to identify if anticoagulation treatment is strictly necessary and which anticoagulant treatment is more appropriate for each patient, choosing between low-weight heparin and oral anticoagulants, according also to possible drug−drug interactions (Kraaijpoel et al. 2018). Invasive HF treatments are questioned in the HF-cancer population, such as ex novo electronic device implantation in patients with cardiac failure with diagnosis of new-onset malignancies (Singh et al. 2019), considering that implantation is vetoed with less than 1 year life expectancy (Ponikowski et al. 2016). For HF-cancer patients with life expectancy of 2 or more years, a valid alternative could be treatment with left ventricular assistant devices (Viganego et al. 2016; Ameri et al. 2018). Considering that the presence of cancer is an exclusion criterion for the heart transplant list, cardiologists and oncologists should also meticulously assess every HF-cancer patient in need for heart transplantation (Meijers and Moslehi 2019), scrupulously evaluating life expectancy and prognosis for each individual (Ponikowski et al. 2016; Ameri et al. 2018). On the other hand, after the heart transplant, patients need to be administered with lifelong treatment with immunosuppressant drugs, well-known for increasing the risk of developing new-onset cancer. However, it is not quite understood if patients with recent diagnosis of malignancies are more prone to develop new caner compared to the general population when administered with immunosuppressors. As stated above, HF itself usually is among the exclusion criteria for oncological trials, leading to scarce information on the management of many antineoplastic protocols in patients with cardiac conditions, including dosage

96 Cancer in the Heart Failure Population adjustment and adverse reactions. Recently, the SAFE-HEaRt trial has been investigating the efficacy and safety of administering HER2 inhibitors in patients with mildly reduced HF (Lynce et al. 2017; Angelini et al. 2019). Obviously, more studies are required to define optimal cardioprotective and surveillance strategies to adopt in HF patients who develop cancer and which cardiac patients must withdrawal from oncological treatments due to excessive risks. In conclusion, HF patients who develop cancer should receive the most appropriate HF therapies to be able to be administered with the best oncological protocol available: neither HF should burden anticancer treatment nor the contrary. Unfortunately, Gross et al. (2007) showed that HF patients with colon-rectal malignancies are less likely to be administered with adjuvant oncological protocols and, thus, present worse 5 years prognosis, compared to non-HF patients with the same cancers. By contrast, HF in patients who are diagnosed with cancer should not be undertreated, considering that the optimized treatment for cardiac failure is composed of a complex set of drugs for both the specific heart disease and for its comorbidities, such as dyslipidemia, dysthyroidism, and diabetes mellitus (Ponikowski et al. 2016). Drug interactions between cardiovascular and oncological drugs should be explored in order to suspend or modify dosages when necessary. Moreover, HF patients’ homeostasis might be impaired by the oncological condition, considering that both cancer itself and antineoplastic treatment might induce vomiting, diarrhea, or other endocrinological alterations, leading to electrolyte impairment which has to be promptly addressed by cardio-oncologists. In particular, HF patients with cancer diagnosis might need temporary dosage adjustments and treatment suspension. However, it is important to tailor therapy for each patient, trying to avoid HF specific therapy undertreatment or definitive suspension. All things considered, each HF patient who develops cancer has to be treated as a unique case, both oncological and HF therapies need to be tailored to the specific individual and clinicians should carefully risk-stratify patients in order to identify those more exposed to the risk of developing new-onset malignancies and provide adequate screening programs.

6.5 Conclusions Nowadays, it is clear that HF and cancer are not only linked by common pathophysiological mechanisms, but recent data reinforce the hypothesis that cardiac failure itself might promote tumorigenesis. The higher incidence of cancer in HF patients compared to the general population is consistent

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with those new findings. Moreover, tumor development in patients with pre-existing HF further complexifies both oncological and cardiological management. Not only both cancer and HF are burdened by independent increase in mortality risk but may also interfere with one another’s treatment, resulting in a further impairment of patients’ prognosis. A tight collaboration between cardiologists and oncologists is strongly recommended, aimed at improving patients’ quality of life and survival. Both professional categories need to rely on one another in order to avoid suboptimization or suspension of either cardiac or antineoplastic treatments. Each patient should be considered as a unicum and a multidisciplinary approach, including specialized nurses, cardiac rehabilitation specialists, psychologists, and palliative care professionals, should be always preferred (Meijers and Moslehi 2019). In the HF population, cancer surveillance programs should be considered to screen those who are more exposed to develop malignancies and intervene as promptly as possible. Nevertheless, more studies on possible cancer biomarkers associated with HF are needed (Kitsis et al. 2018). Unfortunately, current knowledge being still limited, clinicians need to base most of their clinical decisions on populations other than HF-cancer patients.

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7 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology Christian Cadeddu Dessalvi, Martino Deidda, Antonio Noto, Giuseppe Mercuro Department of Medical Sciences and Public Health − University of Cagliari, Italy *Correspondence to: Christian Cadeddu Dessalvi, MD Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy Email: [email protected] KEYWORDS: Biomarkers; Cardio-Oncology; Cardiotoxicity; Metabolomics; Precision Medicine.

7.1 Introduction In the diagnosis of chemotherapy cardiotoxicity, biomarkers were immediately identified as the possible best tool that would allow the finest monitoring and prevention of this phenomenon. Cardiac biomarkers may be useful at different phases of cancer management, like estimating baseline risk prior to cancer treatment, during treatment in monitoring for early toxicity and to evaluate late side effects in survivors. However, compared to initial high expectations, most biomarkers showed inconclusive results as effective tools in the early diagnosis of cardiotoxicity (Zamorano et al. 2016). CV toxicity can be acute, subacute, or present itself years after chemotherapy or radiotherapy, involving several cardiac structures leading to heart failure (HF), valvular heart disease, coronary artery disease, arrhythmias, and pericardial disease. Biomarkers have been tested in different cancer settings showing 107

108 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology

Figure 7.1 Timing of cardiotoxicity detection by conventional biomarkers and metabolomics.

encouraging results mostly in the prediction of left ventricular dysfunction and consequently in the development of HF (Cardinale et al. 2015). Left ventricular impairment and HF is the most common cardiotoxicity deriving from cancer therapies. However, definition in trials and routine clinical practice vary and currently the role of cardiac biomarkers appears not clearly defined. Cardiac troponins (cTn) (both troponin I and troponin T) are the most studied biomarkers for the detection of early myocardial injury; however, a standardized timing of the blood samples and a specific cutoff for its clinical use has not been defined (Cardinale et al. 2000). To date, cardiotoxicity surveillance involving the detection of cardiac biomarkers appears to have a role only if combined with serial imaging, providing the most sensitive strategy to detect early toxicity and guide cardioprotective interventions (Fallah-Rad et al. 2011). Using this combined approach, cardiologists could support ongoing oncology treatment to completion in >85% of patients referred with cardiotoxicity from their current cancer treatment (Pareek et al. 2018). More recently, the new omics sciences are emerging in this context with promising results. Of all, metabolomics has provided the first encouraging results in animal models (Deidda et al. 2019) and the first data on small clinical trials show the ability of metabolomics to identify patients who are undergoing significant early cardiovascular toxicity (Cocco et al. 2020) (Figure 7.1).

7.2 Metabolomics Metabolism, from the Greek μεταβολή or “change,” is a term that indicates the set of life-sustaining chemical reactions by which the body converts

7.2 Metabolomics 109

nourishment into energy. It has a crucial role in balancing cellular physiology reactions (cellular growth and energy production) and cellular defense against metabolic aberrations (such as oxidative stress, toxicants, etc.). The biological mechanisms behind these processes are highly complex depending both on the genetic and epigenetic asset, and their final products are molecules named metabolites (Nielsen 2017). Metabolites are low-molecular weight chemical with a mass range between 50 and 1500 daltons (Da), being either metabolic intermediates or metabolic end products, resulting from the cellular metabolism. Indeed, metabolites neither correlate “one-to-one” with genes nor originate from a single biochemical reaction; rather, multiple metabolites can originate from one enzyme (Zelezniak et al. 2014). In the human body, metabolites could result from human or microbial metabolism, environment, and diet. The identification of single metabolites in biological samples, such as glucose, creatinine, and many others, have been considered important for the diagnosis and monitoring of various diseases, such as diabetes mellitus, and kidney disease. However, for modern medicine, this approach is largely incomplete, hampering an overview of molecular mechanisms involved in a given disease. Metabolomics recognizes and measures metabolites detectable in a given biological sample, thus connecting genotype and phenotype by integrating the individual’s epigenetic and genetic variation, environment, microbiota, and lifestyle each other (Holmes et al. 2008; Baker 2011). The metabolomic approach consists of three sequential steps: (Zamorano et al. 2016) samples collection and storage, (Cardinale et al. 2015) samples analysis using an experimental technique, (Cardinale et al. 2000) and data analysis. Regarding the first step, the following rules should always be applied: collection of samples in a sterile container containing micromolar quantities of inorganic bacteriostatic agents such as sodium azide (0.01–0.1%) to avoid metabolic alterations due to bacterial metabolism; quick centrifugation of the samples at high speed to eliminate cellular debris, including active enzymes that can modify the metabolic content; early freezing of the samples at very low temperatures (−40 °C; −80 °C), up to the analysis; thawing the samples on ice to avoid rapid and harmful temperature variations (Gika et al 2008). Regarding the second step, many different technological platforms are used, such as highperformance liquid chromatography coupled with mass spectrometry (LCMS), gas-chromatography coupled with mass spectrometry (GC-MS), and proton nuclear magnetic resonance spectroscopy (1H NMR). Based both on the technology performed and on the experimental design, a further classification concerns untargeted and targeted metabolomics. The former analysis includes all the detectable metabolites present in a biological

110 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology sample, while the latter studies only specific class of metabolites, such as lipids, carbohydrates, organic acids, amino acids, and so on (Ribbenstedt et al. 2018). Finally, data analysis produces complex data matrices, consisting of the quantitative measurement of several hundred metabolites, which are subsequently analyzed with chemometrics methods, multivariate statistical tools that allow the extraction of biological, and physiological and clinical information. The conversion of metabolic patient-specific data into actionable clinical applications takes more than a robust platform technology. Despite the importance to interpret metabolomics data by the comparison between the individual metabotype with that of a reference population, clinical metabolomics testing should be based on an individualized approach (Hoffmann et al. 2011; Moyer et al. 2019). Since biomarkers can be considered the key to the individualized treatment and precision medicine, metabolomics is basic for the discovery of novel biomarkers potentially useful in clinical practice and for deciphering alterations of the cellular functionality and metabolic pathway perturbations due to a given disease (Tolstikov et al. 2020). In fact, the individual metabolic profile, also called metabotype, is crucial to identify the susceptible individuals to cardiotoxicity, given the fact that the same pathological injury may originate different responses among individuals. An example is the diagnosis of heart failure (HF) due to cardiotoxicity (CTX), a leading cause of death worldwide. In a homogeneous group of such disease, usually treated by a conventional therapy, some of them may be found different only from the metabolomics point of view, suggesting that the disease and the response to the treatment are only identifiable at the molecular basis (Deidda et al. 2019). Metabolomics findings suggest that energy metabolism is a critical target in the development of this CTX form. Therefore, research aims to investigate these pathways for the identification of early markers of CTX and the development of innovative cardioprotective agents.

7.3 Metabolomics in Cardio-Oncology The first study in this setting has been conducted by Andreadou et al. performing an NMR metabolomics profile of acute doxorubicin (DOX) induced CTX in a mouse model. After 3 days of DOX administration, a time sufficient to determine acute CTX at the cardiomyocyte level, the authors acquired 1H-NMR spectra of aqueous myocardial extracts. Authors found increased myocardial levels of acetate and succinate in DOX-treated samples, whereas branched-chain amino acids decreased, concluding that acetate and succinate could be useful as CTX biomarkers; moreover,

7.3 Metabolomics in Cardio-Oncology 111

oleuropein, a phenolic antioxidant derived from olive tree with documented cardioprotective effects, could reduce the distress of the energy metabolism (Andreadou et al. 2009). The same researchers confirmed that oleuropein could have a role in the CTX prevention. In this study, metabolomic data were analyzed together with cardiac geometry and function evaluated by echocardiography, cardiac histopathology, nitroxidative stress, inflammatory cytokines, NO homeostasis (iNOS and eNOS expressions), and kinases involved in apoptosis (Akt and AMPK). The authors found a) reduced fractional shortening and left ventricular wall thickness in the DOX group, b) altered protein biosynthesis, c) an imbalance between the expression of iNOS and eNOS, and d) a perturbation in energy metabolism. However, Oleuropein seemed to prevent the DOX-mediated CTX inducing AMPK activation and iNOS suppression (Andreadou et al. 2009). It is noteworthy that, on the bases of identified metabolites, energy production pathways resulted involved in the CTX development in both the studies of Andreadu (Andreadou et al. 2009, 2014). The centrality of these energetic pathways was confirmed by a GC– MS metabolomic study in which Tan et al. (2011) identified a fingerprint consisting of 24 metabolites involved in glycolysis, citrate cycle and metabolism of some amino acids and lipids in this rat model of DOX-induced CTX, evaluated as increases in creatine kinase (CK), CK-MB and lactate dehydrogenase (LDH) 3 days after DOX administration. In order to reduce pirarubicin (THP) derived CTX, it has been developed a liposomal drug delivery system. Cong and colleagues studied the metabolic footprint of Sprague-Dawley rats’ urine after three successive doses of liposome powder THP (L-THP) or free THP (F-THP). The metabonomic analysis confirmed that L-THP caused minimal metabolic changes compared to F-THP; moreover, subsequent doses of THP determined severe metabolic alterations, particularly at the level of energy production pathways. In detail, in the treatment groups was observed a significant downregulation of citrate (Krebs cycle), lactate (glycolysis), D-gluconate-1-phosphate (pentose phosphate), N-acetyl glutamine, and N-acetyl-DL-tryptophan (amino acid metabolism) (Cong et al. 2012). A mouse model of CTX, analyzed by ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC–QTOF-MS), identified 39 biomarkers able to point out development of CTX, defined as severe heart damage evaluated by biochemical analysis and histopathological assessment. To filter out the biomarkers specific for CTX, the fingerprint was corrected for hepatotoxicity and nephrotoxicity, thus obtaining a panel consisting of 10 highly specific metabolites; among them,

112 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology the most strongly specific resulted L-Carnitine, 19-hydroxydioxycortic acid, lysophosphatidylcholine (LPC) (14:0), and LPC (20:2). Furthermore, this panel showed to change before biochemical and histopathological alterations (Li et al. 2015). To identify the early biomarkers of CTX induced by DOX treatment, a metabolomic study applying mass spectrometry and NMR spectroscopy was designed and carried out on male B6C3F1 mice, to whom 3 mg/kg DOX dose or saline were administered weekly for 2, 3, 4, 6, or 8 weeks; one week after the last dose, animals were sacrificed. At the myocardial level, an increase of 18 amino acids and 4 biogenic amines (acetylornithine, kynurenine, putrescine, and serotonin) was detected after a cumulative dose of 6 mg/kg; on the contrary, authors identified a myocardial lesion only at a cumulative dose of 18 mg/kg, and the cardiac pathology was highlighted at 24 mg/kg of cumulative dose. The metabolic analysis also revealed altered plasma levels of 16 amino acids, 2 biogenic amines (acetylornithine and hydroxyproline), and 16 acylcarnitines, whereas 5 acylcarnitines resulted in decreased cardiac tissue. It is important to highlight that plasma concentrations of lactate and succinate, two intermediates of the Krebs cycle, were significantly modified after a very low cumulative dose (6 mg/kg) (Schnackenberg et al. 2016), well before of the histological and clinical evidence. To identify biomarkers of CTX, samples collected from rats after cyclophosphamide (CY) treatment were analyzed using UPLC–Q-TOF-MS. Metabolomic analysis showed altered levels of a dozen metabolites in the plasma of CY-treated group after 1, 3, and 5 days in comparison of the control group. Authors hypothesized that these molecules, involved in the metabolism of glycerol phospholipid and linoleic acid, may be implicated in the CTX induced by CY and suggested that it could determine increased myocardial oxygen consumption and impaired fatty acid β oxidation (Yin et al. 2015). In a study designed to evaluate the effects on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of DOX for 2 days or 6 days in a repeated way, 1H-NMR spectroscopy was used to profile the culture medium. A single DOX exposure did not result in changes of the extracellular metabolites, whereas repeated exposures determined an impairment in the utilization of pyruvate and acetate, with an accumulation of formate. Moreover, during the washout from DOX were demonstrated a reversible effect and a restored utilization for pyruvate by hiPSC-CMs, while formate and acetate presented an irreversible effect. On these findings, the authors proposed a role for pyruvate, acetate, and formate as biomarkers of CTX induced by DOX (Chaudhari et al. 2017). In order to identify a biomarker of both DOX-induced CTX and cardioprotection by dexrazoxane (DZR), 96

7.3 Metabolomics in Cardio-Oncology 113

BALB/c mice were randomly divided into two groups (tumor and control), each split into four treatment subgroups (control, DOX, DZR, and DOX plus DZR). A weight loss >20% established the moment to euthanize the animals. Metabolomic analysis showed a DOX administration fingerprint constituted by an increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, and 3-hydroxybutyrate levels and a decrease in glucose, glutamate, cysteine, acetone, methionine, aspartate, isoleucine, and glycylproline levels. For its part, DZR treatment caused increased levels of lactate, 3-hydroxybutyrate, glutamate, and alanine and decreased levels of glucose, trimethylamine N-oxide, and carnosine. It is noteworthy that the authors suggested that their findings seem to confirm the importance of altered energy metabolism in the development of CTX (QuanJun et al. 2017). Recently, tyrosine kinase inhibitors (TKI) have become an effective option for the treatment of a wide range of malignancies. CTX is a severe complication also of TKI use, probably due to their impact on specific cardiac metabolic pathways, with which this class of drugs interacts. To investigate the cardiotoxic effects of sorafenib, a non-targeted GC–MS metabolomics analysis was applied to the heart, skeletal muscle, liver, and plasma collected from FVB/N mice treated for two weeks with daily administration of sorafenib or vehicle control. Compared to controls, echocardiography of sorafenibtreated mice showed systolic dysfunction, while metabolomic analysis found significant changes in 11 metabolites, including a marked alteration in the metabolism of taurine/hypotaurine (Jensen et al. 2017a). Another study aimed to evaluate the pathophysiology of CTX induced by TKIs was conducted on 10/group female FVB/N mice treated every day with sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle (control group) daily for a time of two weeks. The authors carried out a non-targeted GC– MS based metabolomic analysis on the specimens of heart, skeletal muscle, liver, and on serum. The sunitinib-treated mice showed, in comparison with the control group, a systolic dysfunction at echocardiography and a significant decrease in levels of docosahexaenoic acid, arachidonic acid/ eicosapentaenoic acid, O-phosphocolamine, and 6-hydroxynicotinic acid at the metabolomic analysis. On the other hand, erlotinib did not determine a decrease in systolic function but only an increase in the levels of spermidine. The authors highlighted that their study suggests a link between CTX due to sunitinib treatment, polyunsaturated FA depletion, and inflammatory mediators (Jensen et al. 2017b). Aimed to investigate the metabolic changes induced in cardiac cells by the exposure of the heart to ionizing radiation, Gramatyka and colleagues studied irradiated human cardiomyocytes using high-resolution magic-angle-spinning

114 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology nuclear magnetic resonance techniques (HR-MAS NMR). The metabolomic analysis found changes in lipids, threonine, glycine, glycerophosphocholine, choline, valine, iso-leucine and glutamate, as well as impaired metabolism of glutathione and taurine. Authors concluded that ionizing radiations are able to alter the c cardiomyocytes metabolic pathways even at low doses, which potentially do not affect cell viability (Gramatyka et al. 2018). A more recent study by Unger and colleagues carried out a metabolomic and lipidomic analysis on male Sprague Dawley (SD) rats sham irradiated or subjected to receive fractionated doses (9 Gy per day × 5 days) of targeted X-ray heart radiation; plasma and left ventricle heart tissue samples were collected and analyzed. Moreover, authors applied high-resolution GC_MS to profile the plasma samples of esophageal cancer patients treated with high dose thoracic RT. Study results showed commonalities between the metabolic alterations induced by radiations in the rat model and in cancer patients, including steroid hormone biosynthesis and vitamin E metabolism. Moreover, these findings were used to develop algorithms able to classify the risk of developing radiation-induced heart disease in patients (Unger et al. 2020).

7.4 Metabolomics Profiling Cardioprotective Strategies In clinical practice, traditional biomarkers have been used to monitor the efficacy of several cardioprotective strategies (Gulati et al. 2017; Avila et al. 2018; Cardinale et al. 2018). The International Cardio Oncology SocietyOne (ICOS-1) trial investigated an ACE-inhibitor as enalapril used in patients receiving anthracyclines either as primary prevention before anthracyclines or after a detection of a troponin rise in a biomarker-guided cardioprotective strategy (Cardinale et al. 2018). The study established that low dose enalapril (mean 5 mg/day) did not affect anthracycline-related increase in troponin, but it did reduce LV remodeling in both study arms. Another primary prevention trial with candesartan (PRADA trial) confirmed in a breast cancer cohort receiving anthracycline the inability to prevent troponin release although reducing adverse remodeling (Gulati et al. 2017). On the contrary, primary prevention with beta blockers administered before anthracycline treatment showed to be able to reduce the troponin rise although not affecting significantly LV remodeling (Gulati et al. 2017; Avila et al. 2018). However, since several studies have shown that in this setting the findings are inconstant based on the type of biomarker and on whether biomarkers are used pre-, during, or post-chemotherapy, more data is needed to reach significant conclusions (Sandri et al. 2005; Cardinale et al. 2017). Moreover,

7.5 Conclusion 115

several studies including ICOS-1 (Cardinale et al. 2018) have demonstrated that troponin may not always be the most suitable biomarker by showing that it is possible for it to rise independently of cardiotoxicity. Metabolomic could be of help also in this setting with promising results to better understand cardioprotection physiopathology, although, so far, only experimental models have been tested. The potential cardioprotective effect of losartan against sorafenib-induced cardiotoxicity has been studied with a GC-MS non-targeted based metabolite profiling of rat plasma conducted together with echocardiographic exam. Sorafenib induced significant alterations in indexes of myocardial contractility and relaxation, reversed by the co-administration of losartan. Sorafenib-induced CTX was characterized by elevation in some metabolites levels, including urea and fatty acids; however, only glycine and lactic acid resulted statistically significant. It is noteworthy that losartan demonstrated to be able to restore these changes, resulting in a significantly reduced glycine, urea, and some fatty acids levels (cis-vaccenic acid, oleic acid, stearic acid, and undecanoic acid). Authors concluded that losartan could be effective in determining a protective effect against CTX induced by sorafenib (Abdelgalil et al. 2020). Yoon and colleagues performed an 1H-NMR-based metabolomic analysis to investigate the cardioprotective effects of spinochrome D (SpD) evaluating its effects on human cardiomyocytes and human breast cancer cells against 24/48 h exposure to 0.1 μM DOX. SpD did not determine any effect on DOX anticancer properties but seemed to protect AC16 cells from its toxicity. Furthermore, SpD was able to determine different mitochondrial membrane potentials and calcium localization between cardiomyocytes and cancer cell lines, suggesting a possible explanation for the observed SpD role against CTX due to DOX administration. A decrease in acetate, glutamine, serine, uracil, glycerol levels, and an increase in those of glutamate, isoleucine, O-phosphocholine, taurine, myo-inositol, glutathione, and sn-glycero-3phosphocholine were found; moreover, glutathione metabolism resulted the most significantly altered pathway by SpD (Yoon et al. 2018).

7.5 Conclusion Metabolomics proved to be an effective tool for the early diagnosis of chemotherapy-related CTX being able to identify the first signs of metabolic pathways alteration (Figure 7.1). Most of the studies seem to point out the changes in energy metabolism as the most affected; however, several other findings show the ability of this technique in establishing a specific metabolic predisposition for antiblastic drug induced CTX.

116 Metabolomics in the Identification of New Biomarkers in Cardio-Oncology The basic and translational metabolomic approach, recognizing specific metabolic profiles related to the risk of CTX, will make a priori stratification and very early identification of the CTX risk possible, well before the onset of significant alterations reported by commonly used biomarkers, which are mostly indexes of occurred cardiac damage. Indeed, studies on animal models and in small cohort of patients seem ready to translate this initial perception of efficacy into clinical evidence. Moreover, great expectations rely on the large number of pathophysiological data provided by metabolomics as well as by other unconventional strategies (Madonna et al. 2015; Tocchetti et al. 2019), to be able to identify a highly effective and individualized therapeutic strategy, able to prevent and treat CTX (Cadeddu et al. 2016).

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8 Imaging in Cardio-Oncology Roberta Manganaro* and Concetta Zito Department of Clinical and Experimental Medicine Unit of Cardiology − University of Messina, Messina Italy *Correspondence to: Roberta Manganaro, MD Department of Clinical and Experimental Medicine Unit of Cardiology - University of Messina, Messina Italy Tel: +39-090-221-2969 E-mail: [email protected] KEYWORDS: Cardiotoxicity; Multimodality Imaging; Echocardiography; Myocardial Strain; Risk Stratification; Follow Up.

8.1 Introduction Cardiovascular (CV) complications in cancer patients present a growing medical problem, causing substantial premature mortality in this population. Myocardial dysfunction and heart failure (HF), frequently described as cardiotoxicity, are the most concerning cardiovascular complications of cancer therapies and cause an increase in morbidity and mortality. Contemporary cardiac imaging plays a pivotal role for baseline risk stratification, timely diagnosis of early CV disease and of cardiac dysfunction, both during and following treatment, for the identification of cancer patients who may benefit from cardioprotective treatments whilst continuing oncology treatment, and prognostication to select cancer patients who may require long-term CV follow-up (Čelutkienė et al. 2020). Echocardiography is a crucial tool in these settings: for risk stratification, at baseline and during follow-up of cancer patients to early identify left ventricular (LV) impairment and closely monitoring cardiac function throughout the oncological treatment. Different definitions of cancer 121

122 Imaging in Cardio-Oncology therapy-related cardiac dysfunction (CTRCD) based on echocardiographic LV ejection fraction (EF) assessment are proposed in guidelines, position statement, and oncology trials (Čelutkienė et al. 2020; Zamorano et al. 2016; Plana et al. 2014). According to the 2016 ESC cardio-oncology position statement, CTRD is defined as a decrease in the LVEF of >10 percentage points to a value 10% (percentage points) for 2D, >5% automatic 3D for 3D from pre-treatment value • 2D/3D GLS, GCS Relative reduction by >10%–15% from pre-treatment value and to below lower limit of normal • LV 2D/3D systolic and diastolic Increase by 15 mL for ESV, 30–35 mL for volumes EDV RV function, pulmonary artery pressure, and volemia • Markers of systolic RV function TAPSE 3 lines of chemotherapy, and cardiac radiation were independent predictors of valve disease. In those treated by chemotherapy, only age >50 years and >3 lines of chemotherapy were associated significantly with valve disease. The authors concluded that AC-containing chemotherapy alone is associated with valvular heart disease due to valve degeneration. It can be postulated that chemotherapy does have direct cellular toxicity in mature cells that do not divide frequently such as

126 Imaging in Cardio-Oncology the myocardium. Perhaps, valvular endothelium can be damaged as well, leading to scarring, leaflet retraction, and thickening, which could cause regurgitation and, eventually, stenosis. Further research need to be done to elucidate this intriguing concept. At this time, it seems prudent to consider valve disease in long-term lymphoma survivors whether they received radiation or chemotherapy or especially both at high doses as a young person (Murbraech et al. 2016). Moreover, in patients with advanced malignant tumors, non-bacterial thrombotic or marantic endocarditis may occur, particularly in left sided valves (Edoute et al. 1997; Eiken et al. 2001). Echocardiography remains the first-line and gold standard imaging modality for the assessment of valvular heart disease, allowing qualitative and quantitative evaluation of both stenotic and regurgitant valves. Patients with significant baseline or changing valvular findings during chemotherapy require more frequent serial echocardiographic examinations. 8.2.4 Pericardial disease Pericardial involvement is quite frequent in oncological patients. It may be secondary to cardiac metastasis or may be a consequence of radiotherapy and/ or chemotherapy (Gaya and Ashford 2005). (18, 19) Several chemotherapy agents were related to pericardial disease: anthracyclines (Casey et al. 2012), cyclophosphamide (Katayama et al. 2009), methotrexate (Savoia et al. 2010), arsenic trioxide (Huang et al. 1998), and, less frequently, 5-fluorouracil (Çalık et al. 2012), docetaxel (Dogan et al. 2017), and tyrosine-kinase inhibitors (Agrawal et al. 2015). Pericardial disease induced by chemotherapy generally manifests as pericarditis, with or without associated myocarditis. Pericarditis can arise acutely during radiotherapy, leading to later pericardial constriction which typically presents over 10 years following treatment. Echocardiography is the first line imaging modality for assessment of pericardial involvement. The echocardiographic findings in these patients may be entirely normal or show clear evidence of a pericardial effusion. The pericardial effusion should be quantified and graded using recognized methods to allow comparisons in subsequent evaluations. Echocardiographic and Doppler signs of cardiac tamponade should be investigated, particularly in patients with malignant effusions. When constrictive pericarditis is suspected, echocardiographic signs of constriction should be explored according to published guidelines (Klein et al. 2013; Cosyns et al. 2015). Other imaging modalities, such as computed tomography or CMR, may be a

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useful diagnostic complement. CMR is particularly helpful in determining the presence of late gadolinium enhancement for the identification of pericardial inflammation.

8.3 Advanced Echocardiography 8.3.1 Myocardial deformation imaging The definition of CTRCD relies on the estimation of EF; however, the known limits of this parameter, especially if obtained by 2D echo, could lead to underestimation of early cardiotoxicity. The normal heart has tremendous recruitable contractile ability, although this is not adequately appreciated (Ewer and Lenihan 2008). Thus, a decrease of EF is a marker of advanced damage, occurring when the heart is no longer able to compensate. Moreover, an interesting study by Thavendiranathan et al. (2014) showed that the interoperator variability of EF was about 10% in the assessment of LV systolic function in patients treated by chemotherapy. Myocardial deformation imaging allows to overcome the uncertain sensibility of LVEF in the evaluation of early impairment of systolic function in patients undergoing anticancer therapy (Sawaya et al. 2011; Jurcut et al. 2008). Myocardial strain can be studied using different ultrasound techniques, including Doppler strain imaging (DSI) and 2D and 3D speckle-tracking echocardiography (STE) (Mor-Avi et al. 2011). DSI was the first method used, and it was more sensitive than LVEF assessment in recognizing LV systolic dysfunction caused by chemotherapy and radiotherapy in adults and children (Hare et al. 2009; Erven et al. 2013). However, this tool exhibited significant limitations, such as low reproducibility, angle dependency, limited spatial resolution, a high sensitivity to signal noise, and high interobserver variability. STE was developed to overcome these limitations. Global longitudinal strain (GLS) has emerged as a new marker of subclinical ventricular dysfunction demonstrating stronger association with prognosis than LVEF (Zito et al. 2018, 2016). It starts to be impaired at an early stage of myocardial damage. However, circumferential strain compensates the reduction in contractile function, resulting in the preservation of LVEF until a later stage (Kraigher-Krainer et al. 2014). Several studies provided information on serial evaluations of cardiac function before and after oncologic treatments by comparing GLS with LVEF (Stoodley et al. 2011; Kang et al. 2013). They found that GLS was the most sensitive and specific measurement for the detection of subclinical myocardial injury early after anthracycline exposure. GLS decreased

128 Imaging in Cardio-Oncology significantly without any reduction in LVEF. Other studies showed that GLS reduction in patients treated with anthracyclines anticipates changes in LVEF, providing fundamental information for an early risk stratification of these subjects (Poterucha et al. 2012; Charbonnel et al. 2017). Negishi et al. (2013) found that the strongest predictor of CTRCD was delta 2D-based GLS measured at the six-month visit, with a cutoff value of 11% point decrease (95% CI 8.3, 14.6). On this basis, the Expert Consensus from the American Society of Echocardiography and the European Association of Cardiovascular Imaging incorporate GLS in the algorithm for the early detection of subclinical LV dysfunction (Plana et al. 2014). According to this document, measurements of GLS during chemotherapy should ideally be compared with baseline value, and a relative percentage reduction of GLS of less than 8% from baseline is not meaningful, but more than 15% from baseline is very likely abnormal. Furthermore, it is strongly recommended to use the same vendor-specific ultrasound machine for longitudinal follow-up of patients with cancer. The regionality of myocardial cardiotoxicity was investigated in 19 children at the midpoint and at the end of their anthracycline treatment. The authors found a septal and apical pattern, which was partially improved at the end of the treatment (Poterucha et al. 2012). These results were recently confirmed in a multicentric study on breast cancer patients underwent anthracyclines-based chemotherapy (Zito et al. 2021). A recent study in 116 patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer supported the serial surveillance using GLS to guide cardioprotection and maintain patients on uninterrupted trastuzumab therapy (Santoro et al. 2019). A definite recommendation on strain-based cardioprotection strategy has not been yet established, even if encouraging results in this field have been obtained (Santoro et al. 2019). The ongoing multicenter, randomized, controlled trail SUCCOUR (Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcome) will provide more insights on the impact of strain-guided cardioprotective therapy in patients at risk of cardiotoxicity during cancer therapy (Negishi et al. 2018). Therefore, GLS surveillance may become a more sensitive strategy for early detection of cardiotoxicity and guide timing of cardioprotective treatment. Finally, other cancer drugs may cause different forms of myocardial toxicity where LVEF reduction is not the primary manifestation. For example, immune check-points (ICIs) cause myocarditis, which can lead to severe HF, cardiogenic shock, and death, but in 38% of cases, they may also occur even

8.4 Three-Dimensional Echocardiography (3DE) 129

without a fall in LVEF. Thus, decision-making concerning the continuation or interruption of such potentially life-saving therapy should no longer rely solely on the single, surrogate echocardiographic parameter (LVEF) which mainly reflects changes in LV volumes, rather than function. GLS analysis in these patients seems to be very promising with a strong correlation with cardiac edema/fibrosis identified by MRI (Čelutkienė et al. 2020).

8.4 Three-Dimensional Echocardiography (3DE) 3DE is likely to become more widely accepted in routine practice due to improved image acquisition and the implementation of semiautomated or fully automated analysis algorithms. The feasibility of 3D LVEF in breast cancer patients with adequate echocardiographic images was 88% at baseline and 66% after AC therapy, reduced during follow-up due to concomitant radiotherapy (RT), left mastectomy, left breast prosthesis, and other patient factors (Narayan et al. 2017). 3DE is more accurate than 2DE in LV volumes and EF measurements, showing a precision that is comparable to CMR. (47) The advantages include better accuracy and reproducibility and lower temporal resolution compared to 2DE. 3DE showed improved accuracy over 2DE in detecting CMR-derived EF < 55% in survivors of childhood cancer (Armstrong et al. 2012; Toro-Salazar et al. 2016). These data may be explained by the fact that 3DE volume measurements are not based on geometric assumptions of LV shape and are not affected by apical foreshortening. Moreover, the automated or semiautomated method for the identification of the LV endocardium, compared with the manual tracing of endocardial contour that is required by the 2D method, provides a more accurate estimation of LV volumes (Jenkins et al. 2009; Muraru et al. 2010). Thus, LV systolic function should be analyzed by 3DE for monitoring of cardiac toxicity when available. However, its dependency on good image quality, time-consuming processing, and the need for operator training limit its widespread use.

8.5 Assessment of Cardiotoxicity Risk and Echocardiographic Surveillance According to Anticancer Treatment The recent European Position Paper on cardiovascular imaging in cancer patients recommends a personalized approach according to patient’s baseline risk of cardiotoxicity in order to balance rational use of resource

130 Imaging in Cardio-Oncology Table 8.2 Assessment of cardiotoxicity risk. Therapy-related factors Patient-related factors Low risk • Lower dose AC (e.g., doxorubicin • Age >18 and rightsided breast cancer), and the absence of shielding designate highest risk and such patients are likely to benefit most from screening (Lancilotti et al. 2013). A baseline comprehensive echocardiographic evaluation is warranted in all patients before initiating the radiotherapy. To assess cardiac structural and functional changes after radiation exposure, available techniques such as echocardiography, CMR, cardiac computed tomography (CT), or SPECT should be used meaningfully within the appropriate clinical indication. 8.8.1 Pericardial disease Echocardiography is the technique of choice in patients with suspected or confirmed pericardial disease. Although it is the first-line imaging modality in diagnosis and follow-up of effusive or constrictive pericarditis, CT and CMR are more sensitive techniques in the detection of specific anatomical abnormalities, such as pericardial thickening and calcification. 8.8.2 Myocardial dysfunction As for chemotherapy-related cardiotoxicity monitoring, echocardiography is the first-line imaging modality to assess LV systolic and diastolic function.

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CMR could help in case of suboptimal echocardiographic image quality or to provide additional structural information. 8.8.3 Valvular heart disease (see also above) Radiotherapy can be responsible for mild left-sided valve regurgitation in the first 10 years post-radiation. Hemodynamically significant (≥ moderate valve disease) is more common >10 years following radiation. Current guidelines recommend echocardiographic surveillance of valvular heart disease (Plana et al. 2014; Lancilotti et al. 2013). 8.8.4 Coronary artery disease The time interval for the development of significant CAD is ~5–10 years post-radiation (King et al. 1996; Hull et al. 2003). Cancer survivors have a more rapid progression of pre-existing atherosclerosis, indicating a potential need for earlier and more aggressive approach in older patients with known coronary artery disease or risk factors. Conversely, in younger cancer survivors, a specific radiationinduced coronary disease, which is different from atherosclerosis, may develop following exposure to high radiation doses. Image-based stress testing, such as stress echocardiography, perfusion SPECT, and CMR, is indicated in irradiated patients who are symptomatic for angina or who develop new resting regional wall-motion abnormalities on a follow-up echocardiogram. CMR is able to directly image epicardial coronary artery stenosis, microvasculature on myocardial perfusion, ventricular function, and viability. With the advent of fast and reliable coronary artery imaging with cardiac CT, CMR is relegated to clinical assessment in younger patients for entities such as anomalous coronary vessels. Because of the high negative predictive value and the inability to assess the hemodynamic significance of detected obstructions, coronary CT angiography is mostly used to rule out the presence of CAD. Therefore, the role of surveillance CT to detect subclinical CAD has been proposed. As in the general population, in RT survivors, the accuracy of CT and calcium score in the diagnosis of significant CAD is high and demonstrates excellent negative predictive value. Moreover, recent data show that the inclusion of CT in the diagnostic workup of stable patients improves long-term prognosis by reducing the incidence of myocardial infarction (Newby et al. 2018). Incidental coronary calcium in thoracic CT for staging and/or RT planning, subsequent follow-up CT and/or PET-CT scans should be reported and quantified. Coronary artery calcification obtained from non-gated chest CT scans correlates well with a 3-mm coronary calcium scan and is incrementally

138 Imaging in Cardio-Oncology associated with worse CV outcomes in cancer patients implicating timely prescription of preventive therapies. However, the timing of CT for surveillance in asymptomatic cancer survivors following high-dose radiation to the chest is unknown and requires further study. During follow-up, a yearly history and physical examination with close attention to symptoms and signs of heart disease is essential. According to current recommendations, in patients who remain asymptomatic, screening echocardiography 10 years after treatment appears reasonable (Lancilotti et al. 2013). In cases where there are no pre-existing cardiac abnormalities, surveillance transthoracic echocardiogram should be then performed every 5 years. In high-risk asymptomatic patients (patients who underwent anterior or left-side chest irradiation with ≥1 risk factors for RIHD), a screening echocardiography may be advocated after 5 years (Lancilotti et al. 2013). In these patients, the increased risk of coronary events 5–10 years after radiotherapy makes it reasonable to consider non-invasive stress imaging to screen for obstructive CAD. Repeated stress testing can be planned every 5 years if the first exam does not show inducible ischemia. The additional role of CMR or cardiac CT depends on the initial echocardiographic results and the clinical indication as well as the local expertise and facilities. However, when the echocardiographic examination yields equivocal findings, these imaging modalities should be considered.

8.9 Conclusions and Future Directions Cardiovascular imaging modalities play a key role in the developing field of cardio-oncology, providing highly sensitive methods for a timely diagnosis of cardiotoxicity. Ideally each patient who must undergo chemotherapy and/or radiotherapy should have a baseline assessment through cardiac imaging. Echocardiography is the modality of choice and 3D echocardiography should be preferred when available for the calculation of volumes and EF. The first examination should be as complete as possible and must include the study of: systolic function, by LVEF and also GLS, diastolic function, heart valves, pericardium, and right chambers. Myocardial deformation imaging and 3D volumetric analysis seem to be optimal techniques to address temporal structural and functional changes during cancer therapy. If the quality of the echocardiogram is suboptimal, CMR is recommended. Later checks ought to have to be guided by the results of the baseline examination, by the patient’s cardiotoxicity risk and by cardiac biomarkers.

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Moreover, patients’ surveillance requires collaborative evaluation by the cardio-oncology team. Suggested detailed algorithms for anthracycline and HER2-targeted therapies aim to improve current clinical practice. Further studies are needed to establish if effective surveillance schemes may change the outcomes of oncology patients by improving their mortality and morbidity.

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9 Venous Thromboembolism in Cardio-Oncology Ciro Santoro MD, PhD & Mario Enrico Canonico MD Department of Advanced Biomedical Science, Federico II University Hospital, Naples, Italy Correspondence to: Dr. Ciro Santoro, MD, PhD Dpt. Of Advanced Biomedical Science, Federico II University Hospital, Naples, Via Sergio Pansini 5, bld 1, 80131 Naples, Italy, Tel: +39 081 7463663, Fax: +39 081 7464255 Email: [email protected] KEYWORDS: Anticoagulation Treatment; Prognosis; Risk Stratification; Thromboprophylaxis; Venous Thromboembolism.

9.1 Introduction Acute venous thrombosis could unveil occult cancer being its first manifestation (Carrier et al. 2008). Approximately 20%−30% of all first venous thrombotic events are cancer related (White et al. 2005; Spencer et al. 2007). Furthermore, the presence of active malignancy is considered a potential factor for unfavorable evolution and proximal progression of distal deep vein thrombosis (DVT). Such risk orientates to a more aggressive anticoagulation management rather than a watchful ultrasound surveillance. In cancer patients, anticoagulation management not only should be aggressive but also last longer given the fact that the presence of cancer is considered a “non-transient” risk factor for venous thromboembolism (VTE), resulting in higher VTE recurrences risk (Ortel et al. 2020). On the other side, cancer may increase the bleeding risk as well, whereas hemorragic events account for higher mortality in oncologic population, occurring in about 10% of solid tumor and higher proportion in patients with hematologic malignancies 147

148 Venous Thromboembolism in Cardio-Oncology (Reeves and Key 2012). Consequently, the simultaneous presence of cancer and VTE put the clinician in a tough spot in terms of balancing the thrombotic and hemorragic risk.

9.2 Biological Mechanism of Cancer-Related Thrombosis Malignancy interacts in an intricate way with hemostatic system enabling both thrombosis and hemorrhage. The main pathway involved in these reactions lies in the activation of tumor-associated clot promoting factors that finally increase the concentration of active thrombin and fibrin. This reaction induces mobilization of platelet, leukocyte, and endothelial cells which in return deploy surface adherence and procoagulant factors (Falaga et al. 2013). Biological mechanism beyond cancer-induced procoagulant status depends on different processes that induce a derangement of the hemostatic system. Cancer procoagulant (CP), highly expressed by proliferating blast cell and by some solid tumors, directly activates Factor X (Kowich et al. 1994; Molnar et al. 2009). Procoagulant tissue factor (TF), overexposed on tumor cell surface, could be vacuolized and released in tumor microparticles rich in TF, which disseminate into the body and causing both systemic and localized thrombotic events. Mice injected with microparticles enriched of TF showed a higher incidence of disseminated intravascular coagulation (DIC)like syndrome, thus enforcing this pathophysiological hypothesis (Falanga et al. 2012). In addition, the production of pro-inflammatory cytokines, like TNF-α and IL-1β, and proangiogenic (mainly VEGF and FGF) by malignant cell further contribute to the procoagulant status by inducing cell-adhesion and vascular cells activation (Falanga et al. 2009) (Figure 9.1).

9.3 Epidemiology and Risk Stratification The occurrence of cancer-related venous thrombosis is estimated to be between 20% and 30 % among all the venous thromboembolic events (Heit et al. 2002; White et al. 2005; Imberti et al. 2008; Braekkan et al. 2010; Gussoni et al. 2013). Recent or active malignant neoplasm increases the risk of venous thrombosis four- to seven-fold, compared to non-oncologic patients, according to the results of several international registries (Heit et al. 2000; Blom et al. 2005; Cronin-Fenton et al. 2010; Walker et al. 2013). In the Multiple Environmental and Genetic Assessment of risk factor for venous thrombosis (MEGA) study, more than 3000 patients experiencing DVT were included in the study. The occurrence of cancer in this population increased the risk of DVT by seven-fold (Blom et al. 2005).

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Figure 9.1 Synergic interaction between primary tumor and activated platelets to develop clot formation due to FXa, thrombin, and TF release from cancer cells.

Furthermore, different cohort studies examined the absolute risk for DVT in cancer patients. The resulting cumulative incidence appears to have wide variation, due to several factors that might influence the observed event, such as time from cancer diagnosis, method of detection for DVT, and follow-up duration. When patients are observed from the time of cancer diagnosis, the cumulative risk for DVT may correspond to 1%−8% within 1−2 years (Sallah et al. 2002; Chew et al. 2006; Vormittag et al. 2009). Over the last two decades, the incidence of venous thrombosis in patients with malignancies showed hyperbolic increment, with a 1.5% incidence in the late 1980s to 4.6% in the early 2000s (Khorana et al. 2007). This increment could be a consequence of different factors; first, the improvement in diagnostic testing and the spread acknowledges of solid link between cancer and venous thrombotic events. Second, the progressive longer survival of cancer population, due to the development of more effective multiple treatments that however held some degree of prothrombotic risk. However, stratifying the risk of DVT in cancer patients according to their background risk may predict the incidence of DVT. In fact, patients with

150 Venous Thromboembolism in Cardio-Oncology Table 9.1 Risk factors for venous thrombosis. Cancer-related Patients-related Type of cancer Older age Stage of cancer Prolonged immobility Time since cancer diagnosis Prior history of venous thrombosis Treatment Black ethnicity Prothrombotic mutation Comorbidities (≥ 3): • Venous thrombosis • Pulmonary disease • Renal disease • Infection • Anemia

high grade or metastatic disease or the presence of prothrombotic anticancer treatment have a two-fold risk increment to develop DVT compared to cancer patients at average risk (Horsted et al. 2012). The risk for developing venous thrombotic events in oncologic setting could depend on several cancer-related and patients-related factors (Table 9.1). Type of malignancy seems to influence the risk of venous thrombosis to the point where high-risk cancer (pancreas, brain, lung, ovarian, lymphoma, myeloma, kidney, stomach, and bone cancer) and low-risk cancer (breast, prostate, malignant melanoma, and testicular) can be identified (CroninFenton et al. 2010). Cancer features of biological aggressiveness, such as early metastatic diffusion and consequential dismal prognosis, correlated with the incidence of venous thrombosis (Wun and White 2009), as evidenced by Tim et al. who showed a positive association between incidence rates of venous thrombotic events plotted against 1-year relative mortality for different types of cancer (Timp et al. 2013). In a Danish cohort study, which included cancer patients at first diagnosis, 57,591 oncologic patients were enrolled and, among them, 1023 experienced VTE. In a subanalysis, the relative risk of thrombotic events progressively increased along with the tumor stage, with an adjusted relative risk (aRR) of 2.9 for stages I and II and an aRR of 7.5 and 17.1 for stages III and IV, respectively (Cronin-Fenton et al. 2010). Similarly, tumor grading appears also to play a role in the association of cancer and VTE as shown by the Vienna Cancer and Thrombosis Study, where 747 patients with solid tumors were investigated, looking for VTE occurrence. In this study, the presence of high-grade tumor (G3−G4) exposed the patients to a higher risk of VTE compared to those with low grade (G1−G2) (hazard ratio, 2.0; 95% CI, 1.1−3.5; p = 0.015). Another debated risk factor for VTE in cancer is the higher incidence of thrombotic events in the first months after cancer diagnosis (Ahlbrecht et al.

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2012). The determinants behind this phenomenon can be detected by observing the clinical evolution of the disease. In the early phases after cancer diagnosis, patients start cancer treatment, whose protocol frequently includes loading dosage that may determine prothrombotic mechanism. On the other hand, in the late phase, anticancer treatment may induce either cancer regression, when efficacious, or death, in the presence of unfortunate prognosis. In both of these cases, the incidence of DVT observed will inexorably fall. As mentioned above, treatment may paradoxically increase the occurrence of DVT, as is the case of hormonal therapy and its boosting effect on venous thrombotic risk, especially in breast cancer (Clahsen et al. 1994). In gastrointestinal cancer, the use of cisplatin containing regimen either alone or in combination with epirubicin revealed higher cumulative incidence of VTE (Starling et al. 2009). Recent chemotherapy protocol with monoclonal antibody (i.e., bevacizumab) (Nalluri et al. 2008) and immunomodulatory drugs (i.e., lenalidomide) (Hirsh 2007) are also factors that might increase the risk of venous thrombosis. Supportive therapy for prophylaxis or treatment of anemia in cancer patients frequently associated with concurrent antineoplastic therapy regimen such as erythropoiesis-stimulating agents and red blood cell transfusion increase the risk of thrombo-embolic events as demonstrated in a metaanalysis that reviews 57 trials on cancer patients (Bohlius et al. 2006). In the oncologic setting, besides cancer-related risk factor, patients-related risk factors too could play a role in increasing the risk for venous thrombotic events. The main patients-related risk factors in this setting are age, history of previous venous thrombosis, and comorbidities. Among the latter, arterial thromboembolism, pulmonary and renal disease, infection, and anemia showed to elevate the risk of thrombosis (Horsted et al. 2012). In patients with colorectal cancer, the concomitant presence of more than three chronic comorbidities condition increases the risk of venous thrombosis of two-fold within 1 year after the diagnosis (Alcalav et al. 2006). Other common risk factors for venous thrombosis in non-cancer population that may recur in this context, such as prolonged immobility after a surgical treatment, placement of central venous catheters, or prothrombotic mutations, should also be a concern as risk factors for thrombosis in cancer patients (Blom et al. 2005; Dentali et al. 2008).

9.4 Clinical Presentation Cancer-related thrombotic events usually interest the venous side and manifest clinically in a broad spectrum of condition, also addressed as Trousseau’s syndrome, named after the French physician who first described the

152 Venous Thromboembolism in Cardio-Oncology association between thrombosis and cancer. This syndrome includes venous and arterial thrombosis, non-bacterial thrombotic endocarditis (NBTE), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD). Venous thrombosis usually interests lower limbs and their clinical presentation in cancer patients may not differ from those patients without cancer (Figure 9.2). Beyond that, cancer related DVT may manifest in several sites (ileocaval, portal or extrahepatic, mesenteric, upper limb veins, migratory superficial thrombophlebitis, etc.), whose singularity should call attention on possible unknown malignancies (Blom et al. 2006). Mieloprolipherative neoplasm (MPN), for instance, may first manifest through cerebral and splanchnic veins thrombosis (i.e., Budd−Chiari syndrome and portal vein thrombosis) (Reikvam and Tiu 2012). Furthermore, in hematologic malignancies, disarrangement of the microcirculatory system generates a broad spectrum of manifestations such as erythromelalgia, cerebrovascular disorder, and non-bacterial thrombotic endocarditis (NBTE). NBTE, frequently associated with MPN, can also be observed in solid tumors, occurring in up to 1.3% of patients dying of cancer. It embodies a cardiac manifestation of hemostatic

Figure 9.2 (A) Not-occlusive deep venous thrombosis of the right common femoral vein with no compression ultrasound (left panel) and with compression ultrasound (right panel, CUS positive, only partial compressibility). (B) On the left, superficial venous thrombosis of the right greater saphenous vein (CUS positive). On the right, superficial venous thrombosis of collaterals of the right greater saphenous vein.

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derangement, as a result of platelets and fibrin aggregation on cardiac valves (Sanon et al. 2011), which could be responsible for arterial thromboembolic events because of vegetation shed displaced peripherally and causing acute vascular occlusions and ischemia. Additionally, the presence of central catheter placement in the upper limb, used for therapeutic purpose, might partially explain the higher frequencies of upper limb DVT in cancer. Data about arterial thromboembolic events are also present, despite limited, mainly affecting upper and lower extremities and cerebral vasculature (Arboiix 2000). The incidence of these events is estimated to be around 2%−5%, but it might vary depending on the type of tumor and chemotherapeutic protocol utilized. Catastrophic systemic activation of the coagulation cascade may lead to disseminated intravascular coagulation (DIC) that will eventually lead to multi-organ failure and increased risk of major and fatal bleeding due to consumption of clotting factors and platelets. DIC is frequently associated with hematologic malignancies such as acute leukaemias (Sanz et al. 2009).

9.5 Recurrent Venous Thrombosis and Treatment in Cancer Population Cancer patients held an elevated risk of recurrent venous thrombosis, with a two- to three-fold increase risk of recurrence compared with noncancer patients (Prandoni et al. 1996, 2002; Trujillo-Santos et al. 2008). Of note, Prandoni et al. observed a higher incidence of recurrent venous thromboembolism despite the anticoagulation therapy in cancer patients compared to non-cancer population, along with higher risk of major bleeding. Recurrence and bleeding occurred predominantly during the initial management and primary anticoagulation treatment, being related with the extent and severity of cancer rather than anticoagulation treatment intensities outside the therapeutic range (Prandoni et al. 1996). Prediction scores like the Ottawa prognostic score have been developed to assess the risk of recurrence of venous thrombosis in cancer population. Based on four predictors (gender, primary tumor site, stage, and number of prior thrombotic events), the Ottawa score differentiates patient at low risk of recurrence (4%) from those at increased risk (16%) (Louzada et al. 2012). The selection of patients who have a balanced risk-benefit profile for initiation of anticoagulation is complex, given individual patient goals and preferences, changing prognosis of specific cancers, common comorbidities, potential drug–drug interactions, underweight states, and competing

154 Venous Thromboembolism in Cardio-Oncology risks of morbidity and mortality (Mosarla et al. 2019). It stands to reason that the occurrence of cancer affects heavily all the three phases of the anticoagulation management of DVT; initial management (consisting in the first 5−21 days), primary treatment (the 3−6 months that follow the initial management), and secondary prevention (whose duration depends on VTE recurrence) as classified by the recent Guidelines for management of venous thromboembolism, (Spencer et al. 2007). In the pre-DOAC era, clinical trials in this population compared LMWH monotherapy with LMWH-bridged warfarin. International Society on Thrombosis and Haemostasis (ISTH) and National Comprehensive Cancer Network (NCCN) 2018 guidelines recommend LMWH as standard of care in treating cancer-associated VTE with fondaparinux and unfractionated heparin as alternative treatment options, compared to oral anticoagulant treatment with warfarin (Lee et al. 2003, 2013; Streiff et al. 2018). Furthermore, parental delivery has the advantage of avoiding gastrointestinal (GI) absorption that might be altered by emetogenic cancer treatment and or by surgical treatment. 2019 ASCO Clinical Practice Guideline Update (Key et al. 2018) underscored the importance of risk stratification for VTE risk and of effective treatment to reduce the risk of VTE recurrence and mortality. Of note, direct anticoagulants (DOACs) have been added as an option for both prophylaxis and treatment, based on the results of recent trials that compared LMWH with DOACs in cancer related VTE (Raskob et al. 2018; Young et al. 2018; Agnelli et al. 2020; McBane et al. 2020). In both Hokusai VTE Cancer study and in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) pilot study, the efficacy of edoxaban and rivaroxaban, respectively, appeared to be more effective in reducing VTE recurrence, at the expense of higher incidence of bleeding events when compared to LWMH. Those events seemed to be particularly higher in those cancer patients with GI malignancies. The efficacy of apixaban in reducing the risk of DVT recurrence was shown in the Caravaggio trial, in which 1155 cancer patients were randomized to receive monotherapy with either apixaban or daltaparin for 6 months. Apixaban showed to be non-inferior for the treatment of cancer associated venous thromboembolism in the absence of increased risk for major bleeding (Agnelli et al. 2020). Moreover, the possibility of an “oral only” loading dosage during the initial management (rivaroxaban 15 mg BID for 21 days or apixaban 10 mg BID for 7 days) results in a facilitate management of anticoagulation therapy, avoiding the parental lead in and bridging with heparin.

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Anticoagulant treatment DOACs provide a reasonable alternative to LMWH in the treatment of VTE in cancer patients; however, particular care should be spent to monitor bleeding events, especially gastrointestinal or urinary (Wojtukiewicz et al. 2020).

9.6 Prognosis The concomitant presence of cancer and thromboembolic event reduces the survival rate of five-fold when compared to thrombotic event alone at 1 year (Heit et al. 2002). On the other hand, the survival rate of patients with cancer and venous thrombosis is more than halved at 1 year if compared to cancer population without venous thrombosis, after matching for age, gender, type of cancer, and year of diagnosis (Sørensen et al. 2000). Indeed, venous thrombosis results to be a significant prognosticator at 1 year for all cancer types, in a large cohort study of more than 230 thousand cancer patients, with and without thrombotic events (Chew et al. 2006). Even though the specific weight of thrombotic events alone on the mortality rates in cancer population is difficult to be estimated, thrombotic event gained the second place as cause of death in patients with cancer, after cancer progression (Khorana et al. 2007).

9.7 Thromboprophylaxis Thromboprophylaxis for primary prevention of VTE has been an important recent clinical and research issue, and its benefit in cancer patients is largely debated. Despite a clear reduction in terms of incidence of venous thrombosis, the increment of major bleeding is a relevant deterrent for the generalization of this kind of management (Ay et al. 2009; Di Nisio et al. 2012). Thus, a possible approach could be to stratify the risk of thrombotic events, to frame those at increased risk of thrombotic events, who could benefit from a prophylactic anticoagulation. Different risk factors and bio-humoral markers have been proposed to increase prediction accuracy for thrombotic events (Iversen et al. 2002; Khorana et al. 2005, 2008; Kröger et al. 2006; Ay et al. 2009; Zwicker et al. 2009; Simanek et al. 2010) and specific efforts have been made to build a comprehensive prediction models to guide decision on thromboprophylaxis. Khorana et al. developed a risk model based on five variables (Table 9.2) assessed from a cohort study of 2701 cancer patients who had to start chemotherapy. Patients displaying a risk score higher than 3 (i.e., high risk group) before starting the treatment showed to have a 6.7% to 7.1% rates of developing venous thrombosis (Khorana et al. 2005).

156 Venous Thromboembolism in Cardio-Oncology Table 9.2 Predictive model for chemotherapy-associated venous thrombosis. Patient characteristic Risk score Site of cancer Very high risk (stomach, pancreas, etc.) 2 High risk (lung, lymphoma, gynaecologic, bladder, testicular, etc.) 1 Prechemotherapy platelet count ≥ 350 × 100/L 1 Prechemotherapy hemoglobin level < 100 g/L or use of red cell growth factors 1 Prechemotherapy leukocyte count > 11 × 100/L 1 Body mass index ≥ 35 kg/m2 1 Rates of venous thrombosis Low risk (score = 0) Intermediate risk (score 1−2) High risk (score ≥3) (Khorana et al. 2005).

Incidence 0.8%−0.3% 1.8%−2% 6.7%–7.15%

Furthermore, improvement in prediction of thrombotic events has been designed adding bio-humoral markers, (i.e., P-selectin >53.1 ng/mL and D-dimer levels >1.44 mg/mL) to the Khorana’s risk model. This expanded model showed a sensitivity of 96% when the patients receive the point score of 1, thus reasonably excluding thromboprophylaxis, and a specificity of 98% for those at higher cutoff point (score ≥5), who may benefit from thromboprophylaxis (Ay et al. 2010). Limitation for this expanded score consists in scarce availability of those bio-humoral marker in daily routine.

9.8 Conclusions Cancer-related venous thrombotic events are a not infrequent manifestation during the history of disease. The right choice between anticoagulation strategy, thrombo-hemorrhagic risk management, and patients’ comorbidities represents a challenge for physicians. An accurate risk stratification to select patients at higher risk of thrombotic events, who would benefit from thromboprophylaxis, should be encouraged. Early identification and treatment of this complication is particularly relevant in the oncohematologic setting, given the substantial impact of venous thrombotic events on morbidity and mortality. Despite increased risk of major bleeding, recently, DOACs provide an attractive alternative to LMWH in the treatment of VTE in cancer patients especially in those without drug interactions, impaired renal function, and low or high body mass index. The large amount of multiple connections between thrombotic pathway and cancer growth needs to be further elucidated in order to provide accurate prognostic score and targeted therapy.

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Conclusions and Remarks Valentina Mercurio, MD, PhD, FISC1; Pasquale Pagliaro, MD, PhD2,3; Claudia Penna, BSc, PhD2,3; Carlo G Tocchetti, MD, PhD, FHFA, FISC1,4,5,6 Department of Translational Medical Sciences, Federico II University, Naples, Italy 2 Departiment of Clinical and Biological Sciences, University of Turin, Torino, Italy 3 Istituto Nazionale per le Ricerche Cardiovascolari, Bologna, Italy 4 Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy 5 Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy 6 Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy 1

Cardio-oncology is an innovative and multidisciplinary field of contemporary medicine. Along with the increasing number of cancer survivors, cardiovascular complications due to cancer therapies are also growing. The data reported in the Pan-European CARDIOTOX-2020 registry underline the primary importance of this fascinating and worrying field of oncology and cardiology (López-Sendón et al. 2020). Indeed, among cancer patients, the prevalence of cardio-vascular (CV) events is many times higher than that in the general population. Widely used anti-tumor drugs, such as anthracyclines (e.g., doxorubicin) and alkylating drugs (e.g., cyclophosphamide), have enormous multi-organ toxigenic potential, particularly cardiotoxic. Yet, several other drugs may contribute to CV damage as analyzed in this book.

163

164 Virtual Reality: Solution to reduce the impact of COVID-19 on Global Economy The most challenging problem facing cardiologists and oncologists is the decision about starting, continuing or chemotherapy in case of development of cardiovascular diseases. This book analyzes some of the most burning questions in Cardio-Oncology. In the various chapters of this book, in addition to in-depth discussions on pathophysiological mechanisms of cardiotoxicity, readers can also find therapeutic measures and strategies to limit cardiotoxic damage in clinical practice. We hope the readers can find this book useful for their daily work as researchers and/or clinicians involved in Cardio-Oncology.

References 1. López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, et al. Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry. Eur Heart J. 2020;41(18):1720-1729. doi: 10.1093/eurheartj/ehaa006.

Index

A Acute Coronary Syndromes 32, 51 Anthracycline 15, 26, 36, 41, 42, 48, 114, 116, 117, 125, 127, 128, 130–132, 134, 135, 139–141, 143–144, 161 Anti-VEGF 25, 41, 43–45, 49 Anticoagulation Treatment 95, 147, 153 Antineoplastic Agents 63, 64 Arrhythmias 28, 63–69, 75–81, 94, 104, 107, 134 Arterial Hypertension 10, 21, 24, 25, 27–30, 36, 41–49, 124, 131, 142 B Biomarkers 7, 17, 20, 77, 91, 97, 102, 107, 108, 110–112, 114, 116–119, 138, 144 C Cancer 2–5, 7–22, 24, 29–39, 41, 42, 44–49, 51–61, 63–65, 67, 69, 73, 74, 76–81, 83–105, 107, 108, 114–117, 119, 121–124, 128–132, 134, 145, 147–161 Cardio-Oncology 1, 2, 4, 6, 8, 12, 15, 17, 19, 21, 34–36, 47–49, 63, 67, 68, 74, 75, 77, 80, 84, 91, 97, 98, 100–102, 107, 110, 118, 121–123, 133, 138, 139, 147

Cardiomyopathy 5, 6, 8, 12, 14, 16, 17, 26, 63, 65, 72, 78, 79, 102, 103, 116, 118, 130, 139, 140, 143 Cardiotoxicity 3, 5, 6, 8, 10–12, 15–21, 23, 32, 35–39, 41–44, 47, 48, 66, 67, 77, 79, 83, 90–93, 98, 99, 107, 108, 110, 115–119, 121, 122, 124, 127–136, 138–145 Cardiovascular Diseases 2, 7, 9, 15, 21, 41, 83–85, 87, 88, 90, 91, 136 Cardiovascular Prevention 31, 41, 49 Cardiovascular Risk Factors 29, 41, 48, 66, 67, 76, 100, 130, 136 Checkpoint inhibitors 2, 4, 11–14, 16–20, 26, 30, 67, 72, 81, 130 Chemotherapy 11, 16, 21, 30, 34–37, 42, 47, 48, 53, 55, 63–66, 68, 69, 75, 77–79, 81, 90, 92, 94, 98, 99, 103, 104, 107, 114–118, 124–128, 130–136, 138–141, 143, 144, 151, 155, 156, 158, 159, 161 E Echocardiography 7, 35, 92, 111, 113, 121–123, 126–131, 133–145 F Follow Up 121

165

166 Index H Heart Failure 3, 9, 10, 12, 13, 15–18, 27–30, 36, 42–44, 48, 58, 63–65, 77, 79, 80, 83–85, 87, 89, 91, 97–99, 101–104, 107, 110, 117, 121, 130, 139, 141, 142, 144 Hypertension 1, 10, 21, 24, 25, 27–30, 33, 34, 36, 37, 41–49, 66, 77, 83, 86, 88, 104, 124, 130, 131, 142

N Neoplasm. 73, 86, 148

I Immune 2, 4–7, 9–20, 26, 30, 31, 34, 38, 59, 64, 67, 72, 81, 128, 130 Inflammation. 1–4, 9–11, 15, 17–20, 26, 34, 54, 67, 90–92, 101, 104, 135

R Risk Stratification 7, 21, 95, 121, 122, 128, 130, 147–148, 154, 156, 159

M Metabolomics 8, 107–110, 113– 116, 118, 119 Multimodality Imaging 121, 136, 140, 143 Myocardial Strain 121, 127, 144

T Thromboprophylaxis 147, 155–156

P Percutaneous Coronary Interventions 51, 57 Precision Medicine. Preventive Cardiology 83 Prognosis 2, 63, 84, 87–88, 91–97, 127, 137, 147, 150, 151, 153, 155, 160

S Surgical Revascularization 59

V Venous Thromboembolism 80, 100, 147, 153, 154, 157–161

About the Editors

Dr Valentina Mercurio got her MD in 2010, her Board in Internal Medicine in 2016 and her PhD in 2019 at Federico II University, Naples, Italy. She is currently Assistant Professor of Medicine in the Department of Translational Medical Sciences, Federico II University, Naples, Italy, since 2019, where she coordinates the Echocardiographic Laboratory of the Cardio-Oncology Unit and of the Heart Failure outpatient unit mostly dedicated to post ischemic heart failure, right ventricular dysfunction and pulmonary hypertension, and in particular to the follow-up of oncologic patient before, during and after undergoing antineoplastic therapies. Her previous studies and ongoing collaborations with Prof. Paul Hassoun and Prof. Monica Mukherjee at Johns Hopkins University, Baltimore, MD, USA are mostly focused on pulmonary hypertension and right ventricular dysfunction, and she has established herself as a Pulmonary Hypertension basic and clinical investigator in Naples. Since 2019, Dr Mercurio is Fellow of the Italian Society of Cardiology and nucleus member of the working group on drug-induced cardiotoxicity and cardioprotection, and a member of the ESC Council of Cardio-Oncology, member of the Heart Failure Association, and of the WG Myocardial Function and of the WG on Pulmonary Circulation & Right Ventricular Function of the ESC, and of the PVRI (Pulmonary Vascular Research Institute). Prof Pasquale Pagliaro, M.D., Ph.D was born in Rossano, Italy, in 1961. He is a full professor of Physiology at University of Turin (Italy) Department of Clinical and Biological Sciences. He is also member of the National Institute for Cardiovascular Researches (Bologna, Italy). Degrees awarded: MD, University of Turin (Italy), Thesis topic: Coronary Pathophysiology, 1988. PhD, University of Turin (Italy), Thesis topic: Endothelial Physiology, 1994. Research Fellowship in MedicineCardiovascular at the Johns Hopkins University Baltimore (USA); Research topic: Coronary and Endothelial Physiology, 1997–99. Research experience/ other activities: Prof Pagliaro is PI in a lab studying coronary physiology and pathophysiology, and cardioprotection. His recent research concerns endothelial factors and other endogenous substances in triggering protective 167

168 About the Editors signaling pathways. Prof Pagliaro’s lab also focusses on redox-signaling and mitochondrial function. Prof Pagliaro served as an Ordinary member of Italian Society of Physiology, The Physiological Society (London), Italian Society of Cardiology, European Society of Cardiology, Italian Society of Cardiovascular Research (SIRC). He served as Vice-coordinator of the nucleus and as member of the working group on drug-induced cardiotoxicity and cardio-protection of the Italian Society of Cardiology. Prof Pagliaro is Past-President of SIRC and the Coordinator of the PhD in Experimental Medicine and Therapy of the University of Turin. Prof Claudia Penna, BSc.D., Ph.D was born in Asti, Italy, in 1967. She is an associate professor of Physiology at University of Turin (Italy) Department of Clinical and Biological Sciences. She is also member of the National Institute for Cardiovascular Research (Bologna, Italy). Degrees awarded: BSc, University of Turin (Italy), Thesis topic: Effect of venom in the isolated heart, 1991. Specialist of Clinical Pathology, University of Turin (Italy), thesis topic: Modulation of cardiac current by Nitric Oxide, 1995, PhD, University of Turin (Italy), thesis topic: Hyperaemic response and Ischemic Preconditioning, 2000. Research experience/other activities: cardioprotection and cardiotoxicity. She is member of Italian Society of Physiology, the Italian Society of Cardiology and European Society of Cardiology. She served as Vicecoordinator of the nucleus and as member of the working group on druginduced cardiotoxicity and cardio-protection of the Italian Society of Cardiology. Prof. Carlo Gabriele Tocchetti got his MD in 1997, his Board in Cardiology in 2001 and his PhD in 2007 at Federico II University, Naples, Italy, and is currently Associate Professor of Medicine and Director of the CardioOncology Unit in the Department of Translational Medical Sciences, Federico II University, Naples, Italy since 2014. He coordinates the Heart Failure outpatient unit mostly dedicated to post ischemic HF, RV dysfunction and Pulmonary Hypertension, and to the follow-up of oncologic patient before, during and after undergoing antineoplastic protocols, and has established himself as a HF basic and clinical investigator. Prof. Tocchetti is Fellow of the Heart Failure Association (HFA), 2020–2022 Chair of the Study Group on Cardio-Oncology of the HFA, of the HFA Translational Research Committee, and of the WG on Myocardial Function of the European Society of Cardiology (ESC), and 2020–2022 Board Member of the ESC Council

About the Editors 169

on Basic Cardiovascular Science (CBCS) and Council of Cardio-Oncology (CCO). His previous studies and ongoing collaborations with Drs Kass and Paolocci at Johns Hopkins University, Baltimore, MD, USA, have helped dissecting the cardiac contractile effects of HNO and the development of a novel HNO donor for treating human heart failure currently used in clinical trials. Hence, the main goal of his lab is to explore pathophysiologic mechanisms and therapeutic targets in cardiac dysfunction, with a particular interest on post-ischemic HF, genetic and inflammatory cardiomyopathies, Pulmonary Hypertension and RV dysfunction, and HF due to antineoplastic therapies, including novel anticancer immunotherapies and biologic drugs employed in inflammatory diseases.